CN105828815A - Treatment of Metabolic Disorders in Felines - Google Patents

Abstract

The present invention relates to one or more SGLT2 inhibitors or pharmaceutically acceptable forms thereof for use in the treatment and/or prevention of a metabolic disorder in a feline, preferably wherein the metabolic disorder is one or more selected from the group consisting of: ketoacidosis, pre-diabetes, type 1 or type 2 diabetes, insulin resistance, obesity, hyperglycemia, glucose intolerance, hyperinsulinemia, dyslipidemia, subclinical inflammation, systemic inflammation, low grade systemic inflammation, hepatic lipid deposition, atherosclerosis, pancreatic inflammation, neuropathy and/or syndrome X (metabolic syndrome) and/or loss of pancreatic beta cell function, and/or wherein remission of metabolic disorders, preferably diabetes remission, is achieved and/or maintained.

Description

Treatment of Metabolic Disorders in Felines

field of invention

The present invention relates to veterinary medicine, in particular to the treatment and/or prevention of metabolic disorders in felines.

Background of the invention

Felines, such as cats, are affected by various metabolic disorders. Many metabolic disorders are known in felines, including hyperglycemia, insulin resistance, diabetes (eg, type 1 or 2 diabetes, or prediabetes), hepatic lipidosis, obesity, hyperinsulinemia, glucose intolerance , ketosis (especially ketoacidosis), dyslipidemia, dysadipokinemia, obesity, subclinical inflammation or systemic inflammation (especially low-grade systemic inflammation), which also includes adipose tissue, X syndrome syndrome (metabolic syndrome), atherosclerosis and/or pancreatic inflammation. Various correlations exist between these disorders. Among these disorders, diabetes, especially prediabetes and type 2 diabetes, as well as hyperglycemia, insulin resistance, hepatic lipidosis, and obesity are of increasing importance for cats. This can be attributed, at least in part, to changes in pet life and husbandry behavior over the past few years.

Diabetes is characterized by disturbances in carbohydrate, protein and triglyceride metabolism based on relative or absolute insulin deficiency. It is a relatively common endocrine disorder in feline species such as cats. The incidence in cats has increased approximately 5-12 times over the past 4 decades to approximately 0.5-1.2%. Several risk factors have been identified: age, obesity, castration and gender. Male, neutered, obese, and elderly (>10 years old) cats are probably at the highest risk of developing diabetes.

The current classification divides diabetes into three categories:

(1) Type 1 which is due to loss of insulin-secreting cell function, for example by immune destruction of beta cells or insulin autoantibodies (juvenile diabetes in humans);

(2) Type 2 which is due to the failure of insulin-stimulated cells to respond adequately to insulin stimulation; it is also associated, for example, with amyloid accumulation in beta cells; type 2 usually develops during the prolonged so-called pre-diabetic phase;

(3) Secondary diabetes can be due to diabetes-causing drugs (such as long-acting sugar steroids (glucosteroid), megestrol acetate, etc.) or due to other primary diseases such as pancreatitis, pancreatic cancer, Cushing's syndrome Cushing, hypothyroidism or hyperthyroidism, growth hormone tumors leading to acromegaly.

Type 2 diabetes in particular is an increasing problem for the cat population in developed countries. Changes in the lifestyles of cat owners are mirrored in their cats -- they are increasingly being kept indoors, have reduced activity levels, and are fed calorie-dense diets that contribute to obesity and predispose them to type 2 diabetes. As these trends continue, the incidence of diabetes in cats will certainly increase accordingly.

Several oral antihyperglycemic drugs have been approved for the treatment of diabetes, especially type 2 diabetes, in humans. These drugs act, for example, by stimulating pancreatic insulin secretion in a glucose-independent or glucose-dependent manner (sulfonylureas/melitidines, or DPPIV inhibitors, respectively), by increasing tissue sensitivity to insulin They act by sex (biguanides, thiazolidinediones) or by delaying postprandial intestinal glucose absorption (alpha-glucosidase inhibitors).

Other measures have been envisaged for treating diabetes and reducing hyperglycemia in humans, including inhibition of the renal sodium-dependent glucose cotransporter SGLT2. SGLT2 in the kidney regulates glucose levels by mediating the reabsorption of glucose back into plasma following blood filtration. SGLT2 inhibition thus induces glycosuria and can reduce blood glucose levels. For example, in WO2007/128749, the compound 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranose-1-yl)-benzene is described as an SGLT2 inhibitor . Many other SGLT2 inhibitors are also known. In WO2011/117295, which concerns the administration of dipeptidyl peptidase IV (DPP-IV) inhibitors to carnivorous non-human animals, in the context of combination therapy with DPP-IV inhibitors, in many other types of Various SGLT2 inhibitors are mentioned in the compounds.

The use of SGLT2 inhibition for the treatment of metabolic disorders in felines such as cats has not previously been envisioned. In felines, drug development for metabolic disorders is much less developed than in humans. Unfortunately, even if treatment or prophylaxis is effective in humans (or other non-feline species), it cannot be concluded that the same measures will be effective, safe, and appropriate in feline species (eg, cats).

Felines are metabolically significantly different from humans or, for example, dogs.

As strict carnivores, felines are not well adapted to dietary carbohydrates. For example feline livers show no glucokinase activity (Tanaka et al., VetResCommun. 2005, 29(6):477-485). In most mammals, such as dogs or humans, hepatic glucokinase acts as a "glucose sensor" allowing hepatic metabolism to respond appropriately to changes in plasma glucose concentrations. In addition, insulin release from the cat's pancreas appears to be less responsive to glucose as a stimulus than most other species (Curry et al., CompBiochem Physiol. 1982. 72A(2):333-338).

Another adaptation of a strict meat-eating diet involves the utilization of protein and fat for energy production—that is, gluconeogenesis. In omnivores, gluconeogenesis occurs mainly under conditions of starvation. In contrast, in obligate carnivores such as cats, gluconeogenesis is continuously active in the liver, regardless of nutritional status, and its activity is higher after meals than in the fasted state (Hoenig et al. AmJ Physiol, 2011 , 301(6):R1798-1807, Verbrugghe et al., Crit Rev Food Sci Nutr. 2012; 52(2):172-182).

Thus, the pathophysiology of metabolic disorders in felines, and their response to medications for such disorders, differs from other species.

Complications of diabetes, such as vision problems and cataracts, are commonly found in dogs with diabetes but rarely in felines.

Oral medications for diabetes with known human drugs such as glipizide (sulfonylurea) work in a small percentage of cats, but these drugs can be completely ineffective if the pancreas is not functioning. To make matters worse, in some studies, glipizide and other oral hypoglycemic drugs have been shown to produce side effects such as vomiting and jaundice, as well as damage to the pancreas and further reduce the likelihood of remission of diabetes in cats. They have also been shown to cause liver damage. Even lower efficacy was reported for other compound classes, namely meglitinides, biguanides, thiazolidinediones, and alpha-glucosidase inhibitors (PalmCA et al., Vet Clin Small Anim 2013, 43:407-415).

Injectable insulin is currently considered the gold standard for feline diabetes treatment. However, cats are notoriously unpredictable in their response to exogenous insulin. No single type of insulin is routinely effective in maintaining blood sugar control, even when administered twice daily. Even when the owner is strictly compliant, control is often poor and secondary problems are common. Many owners find it impossible to achieve an acceptable level of compliance because synchrony of food intake and insulin injection is not possible in most cases. Eventually many cats with diabetes were euthanized due to the disease.

The factors governing patient and owner compliance also vary widely. Oral administration, for example, is still more highly desirable in cats than in humans.

A therapy capable of producing more compliance and thus better glycemic control than existing insulin-based therapies would help attenuate disease progression and delay or prevent the onset of complications in many animals.

Additionally, even when cats with diabetes receive aggressive insulin therapy and achieve clinical remission, this does not necessarily lead to normalization of insulin secretion, pancreatic β-cell function, and/or insulin resistance. Cats remain prone to new onsets of diabetes. It is expected that there will be a treatment of diabetes in felines that would better improve eg insulin resistance and pancreatic beta cell function (Reusch CE et al., Schweizer Archivfuer Tierheilkunde 2011, 153811):495-500).

Thus, there remains a particular need for effective, safe, etc. appropriate treatments for metabolic disorders, including diabetes, in felines.

disclosure of invention

Summary of the invention

The present inventors have unexpectedly found that inhibition of SGLT2 is effective and safe in the treatment and/or prevention of metabolic disorders in felines.

The present invention thus provides the use of one or more SGLT2 inhibitors, or a pharmaceutically acceptable form thereof, for the treatment and/or prevention of metabolic disorders in felines.

In addition, the present invention provides the use of one or more SGLT2 inhibitors or pharmaceutically acceptable forms thereof in the treatment and/or prevention of metabolic disorders in felines, wherein said one or more SGLT2 inhibitors are 1-cyano yl-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranose-1-yl)-benzene (which is hereinafter referred to as compound A) or a pharmaceutically acceptable form thereof.

Compound A has the following chemical formula:

Further aspects of the invention are defined below and in the claims.

The pharmaceutically acceptable form of the one or more SGLT2 inhibitors (preferably Compound A) may be a crystalline complex between the one or more SGLT2 inhibitors and one or more amino acids (such as proline) .

According to the present invention, said one or more SGLT2 inhibitors, preferably Compound A, or a pharmaceutically acceptable form thereof may, for example, be provided for oral or parenteral administration, preferably for oral administration.

The one or more SGLT2 inhibitors (preferably Compound A) or a pharmaceutically acceptable form thereof may be administered at a dose of 0.1 to 3.0 mg/kg body weight per day, preferably 0.2 to 2.0 mg/kg body weight per day, more preferably 0.1 to 2.0 mg/kg body weight per day. 1 mg/kg body weight. Thus, the one or more SGLT2 inhibitors, preferably Compound A, or a pharmaceutically acceptable form thereof, may be prepared for administration of 0.1 to 3.0 mg/kg body weight per day, preferably 0.2 to 2.0 mg/kg body weight per day. Administration, more preferably administration of 0.1 to 1 mg/kg body weight per day.

The one or more SGLT2 inhibitors (preferably Compound A) or a pharmaceutically acceptable form thereof are preferably administered only once a day.

The present invention also provides pharmaceutical compositions comprising one or more SGLT2 inhibitors, preferably Compound A, or a pharmaceutically acceptable form thereof, for use according to the invention disclosed herein.

In the examples provided herein, the therapeutic and/or prophylactic benefit of inhibition of SGLT2 according to the invention was demonstrated experimentally. The experimental data disclosed herein is intended to illustrate the present invention, not to limit the scope of the present invention, which is defined by the following claims.

In particular, the inventors have surprisingly found that the use of an SGLT2 inhibitor according to the invention, preferably compound A, advantageously leads to a reduction in insulin resistance in treated, insulin-resistant felines. That is to say, equivalently, the use of an SGLT2 inhibitor according to the invention, preferably compound A, advantageously leads to an increase in insulin sensitivity in treated, insulin-resistant felines. Insulin sensitivity can be calculated by various surrogate indices, for example during a glucose challenge as a modified BelfioreIndex (1/log(ΔAUC-glucose*ΔAUC-insulin)).

The present invention thus enables improved treatment and/or prevention of diabetes, in particular type 2 diabetes, in felines.

The use of an SGLT2 inhibitor according to the invention, preferably compound A, advantageously leads to a reduction in insulin fluctuations, as measured for example during an intravenous glucose tolerance test (ivGTT), or after any other form of glucose intake, for example After a high carbohydrate diet (postprandial insulin surge) or after a stress-induced rise in blood glucose. More specifically, the use of one or more SGLT2 inhibitors of the invention, preferably Compound A, also advantageously leads to a reduction in second phase insulin secretion, as measured for example during the ivGTT, or after any form of glucose intake Measured, for example, after a meal.

The use of an SGLT2 inhibitor according to the invention, preferably compound A, also advantageously leads to a reduction in plasma levels of non-esterified fatty acids, or an improvement in the elimination of non-esterified fatty acids from the blood stream, as measured for example during ivGTT, or in Any form of test that raises blood insulin is measured afterward.

The use of the SGLT2 inhibitors according to the invention, preferably compound A, thus generally leads to an increase in glucose tolerance, ie to a reduction in glucose intolerance.

Glucose excursions during the intravenous insulin tolerance test (ivITT) were also advantageously improved in felines treated according to the invention compared to untreated animals.

The use of an SGLT2 inhibitor according to the invention, preferably compound A, also advantageously leads to a reduction in body fat, blood leptin levels, and/or respiratory exchange rate (RER). The present invention is also associated with anti-obesity effects and may be particularly beneficial in felines for preventing weight gain and/or causing weight loss. In one aspect, the invention thus allows the control of obesity and/or obesity-related metabolic disorders in felines.

Effects of the use according to the invention (i.e. mentioned above on insulin resistance/sensitivity, insulin fluctuations, second phase insulin secretion, glucose tolerance, elimination of non-esterified fatty acids, body fat, blood leptin levels, Beneficial effects on RER values and/or body weight) are also advantageous in that they allow subclinical treatments in felines, such as the treatment of pre-diabetic states. They thus make it possible to prevent or delay the onset of diabetes in felines. More specifically, they make it possible to prevent or delay certain of the above-mentioned metabolic disorders, symptoms or signs (such as hyperglycemia, glucose intolerance, insulin resistance, abnormal insulin or glucose fluctuations, hyperglycemia, levels of blood non-esterified fatty acids or leptin, obesity and/or loss of pancreatic beta cells) develop diabetes, especially type 2 diabetes.

An additional advantage of the present invention is that the use of one or more SGLT2 inhibitors, preferably Compound A, is effective against metabolic disorders alone, i.e., if desired, the use of one or more SGLT2 inhibitors, preferably Compound A, in cats Monotherapy (ie, stand-alone therapy; ie, no other drug administered to the feline for the treatment or prevention of the same metabolic disorder) was provided in the feline. The invention also allows the possibility of combination therapy with additional drugs (eg additional insulin sensitizing drugs or insulin itself).

A further advantage of the present invention is that, unexpectedly, the use of one or more SGLT2 inhibitors, preferably compound A, is effective against metabolic disorders alone, i.e., if desired, one or more SGLT2 inhibitors, preferably compound A The use of A provides monotherapy (ie, stand-alone therapy; ie, no other drug is administered to the feline for the treatment or prevention of the same metabolic disorder) in felines. The invention also allows replacement of insulin therapy in felines, or combination therapy with insulin additional drugs, such as hypoglycemic drugs. Such combinations advantageously result in a reduction in the dose and/or frequency of insulin or other drug (eg, hypoglycemic drug) administration compared to monotherapy with insulin or other drug in the feline. Most advantageously, felines can be weaned from insulin or other medications. Thus, clinical remission was achieved.

Thus, the use of one or more SGLT2 inhibitors of the invention, preferably Compound A, provides the treatment and/or prevention of the metabolic diseases disclosed herein, including diabetes and/or pre-diabetes, in felines.

The effect of using one or more SGLT2 inhibitors of the present invention, preferably Compound A (such as the above-mentioned effects on insulin resistance/sensitivity, insulin fluctuations, second phase insulin secretion, glucose tolerance, non-esterified fatty acids Elimination, body fat, blood leptin levels, RER values, body weight and/or beneficial effects of hyperglycemia) may be the same or comparable relative to prior administration of one or more SGLT2 inhibitors of the invention, preferably Compound A Felines, and/or can be relative to comparable felines not receiving the treatment (eg, placebo group). In each case, when comparisons are made, the comparisons can be made after a specific treatment period, for example 1, 2, 3, 4, 5, 6 or 7 days; 10 days, 14 days; 2, 3, 4, 5, 6, 7 or 8 weeks; 1, 2, 3 or 4 months. Preferably said treatment period is 4 weeks. Alternatively, the treatment period may be 6 or 8 weeks. Alternatively, the treatment period may be 8 weeks or longer, such as 8-16 weeks.

An additional advantage of the present invention is that one or more SGLT2 inhibitors, preferably Compound A, can be effectively administered orally to felines. Additionally, said one or more SGLT2 inhibitors according to the invention, preferably compound A, may be administered only once a day. These advantages allow for better compliance by the feline being treated and by the owner. This results in better glycemic control of disorders such as diabetes in which felines are receiving insulin therapy. In general, the use of an SGLT2 inhibitor, preferably compound A, according to the invention thus contributes to attenuating (i.e. delaying or arresting) the progression of metabolic disorders and to delaying or preventing metabolic disorders (such as diabetes) and their Onset of complications.

Accordingly, the present invention also provides a pharmaceutical composition comprising one or more SGLT2 inhibitors, preferably compound A, of the present invention for the treatment and/or prevention of metabolic disorders in felines.

The present invention also provides a method for treating and/or preventing metabolic disorders in felines, comprising administering to a feline in need of such treatment and/or preventing an effective dose of one or more SGLT2 inhibitors, preferably Compound A, such as described in this article.

Advantageously, the use of an SGLT2 inhibitor, preferably compound A, according to the invention does not cause hypoglycemia.

The effect of using one or more SGLT2 inhibitors of the present invention, preferably Compound A (such as the above-mentioned effects on insulin resistance/sensitivity, insulin fluctuations, second phase insulin secretion, glucose tolerance, non-esterified fatty acids Elimination, body fat, blood leptin levels, RER values, body weight and/or beneficial effects of hyperglycemia) may be the same relative to prior to administration of the one or more SGLT2 inhibitors (preferably Compound A) of the invention Or a comparable feline, and/or can be relative to a comparable feline that has received, for example, standard insulin treatment (eg, a control group) or is untreated.

An additional advantage of the present invention is that the one or more SGLT2 inhibitors, preferably Compound A, can be effectively administered orally to felines, for example in liquid form. Additionally, the one or more SGLT2 inhibitors of the invention (preferably Compound A) may be administered only once a day. These advantages allow for optimal dosing and compliance by the feline being treated and by the owner.

In general, the use of an SGLT2 inhibitor according to the invention, preferably Compound A, can thus attenuate, delay or prevent the progression of a metabolic disorder such as those disclosed herein in a feline, or can delay or prevent a metabolic disorder and its complications.

definition

All values and concentrations given herein are subject to historically acceptable biases in the biological sciences (within ±10% deviation). The term "about" also refers to this acceptable deviation.

The therapeutic effects disclosed herein (e.g., improvement, reduction or delay in onset of a disorder, disease or condition, improvement, reduction, reduction or delay in any effect, index, marker level or other parameter associated with a disorder, disease or condition) can be used Statistical significance of p<0.05 (preferably <0.01) was observed.

When reference is made herein to a deviation (e.g., increase, increase, exceed, prolong, increase, decrease, lower, improve, delay, abnormal level, or any other change, change or deviation relative to a reference), the deviation may, for example, be relative to The relevant reference value is 5% or more, especially 10% or more, more especially 15% or more, more especially 20% or more, more especially 30% or more, more especially 40% or more More, or more particularly 50% or more, unless otherwise stated. Typically, the deviation will be at least 10%, ie 10% or more. The deviation can also be 20%. The deviation can also be 30%. The deviation can also be 40%. Relevant reference values are generated from groups of reference animals (received placebo treatment instead of the one or more SGLT2 inhibitors (preferably compound A), or untreated).

As used herein, fluctuations (eg insulin fluctuations glucose fluctuations) refer to changes in blood concentration or levels over time. The magnitude of fluctuations (eg insulin fluctuations glucose fluctuations) can be expressed as an area under the curve (AUC) value.

As used herein, the term "active substance" or "active ingredient" encompasses one or more SGLT2 inhibitors (preferably compound A) or any pharmaceutically acceptable form thereof (such as a prodrug or crystalline form) for use according to the present invention use. In case of combination with one or an additional active compound, the term "active ingredient" or "active substance" may also include the additional active compound.

In this context, the expression "in relation to" covers in particular the expression "caused by".

Herein, ivGTT refers to intravenous glucose tolerance test. In ivGTT, 0.8 g dextrose per kg body weight is typically used.

Herein, ivITT refers to intravenous insulin tolerance test. In ivGTT, 0.05 U insulin per kg body weight is usually used.

SGLT2 inhibitors

SGLT2 inhibitors for use in the present invention include, but are not limited to, glucopyranosyl-substituted benzene derivatives, such as described in: WO01/27128, WO03/099836, WO2005/092877, WO2006/034489, WO2006 /064033、WO2006/117359、WO2006/117360、WO2007/025943、WO2007/028814、WO2007/031548、WO2007/093610、WO2007/128749、WO2008/049923、WO2008/055870、WO2008/055940、WO2009/022020或WO2009/022008 .

Additionally, the one or more SGLT2 inhibitors for use in the present invention may be selected from the following compounds or pharmaceutically acceptable forms thereof:

(1) Glucopyranosyl-substituted benzene derivatives of chemical formula (1)

wherein R represents cyano, chlorine or methyl ⁽ most preferably cyano);

R represents H, methyl, methoxy or hydroxy ⁽ most preferably H); and

R ³ represents cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, 3-methyl- But-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethynyl , ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxy-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-propan-1 -yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl , 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxyl, difluoromethoxy, Trifluoromethoxy, 2-methoxy-ethoxy, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano;

wherein ^R is preferably selected from cyclopropyl, ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; and most preferably ^R is cyclopropyl group, or a derivative thereof, wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with a group selected from: (C _1-18 -alkyl)carbonyl, (C _{1 -18} -Alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C _1-3 -alkyl)-carbonyl;

(2) 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranose-1-yl)-benzene, represented by chemical formula (2):

(3) Dapagliflozin (dapagliflozin), represented by chemical formula (3):

(4) canagliflozin (canagliflozin), represented by chemical formula (4):

(5) Empagliflozin (Empagliflozin), represented by chemical formula (5):

(6) Luxogliflozin (Luseogliflozin), represented by chemical formula (6):

(7) Topagliflozin (Tofogliflozin), represented by chemical formula (7):

(8) Ipagliflozin (Ipragliflozin), represented by chemical formula (8):

(9) Ertugliflozin (Ertugliflozin), represented by chemical formula (9):

(10) Agliflozin (Atigliflozin), represented by chemical formula (10):

(11) Repagliflozin (Remogliflozin), represented by chemical formula (11):

(12) Thiophene derivatives of chemical formula (12):

Wherein R represents methoxy or trifluoromethoxy;

(13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene,

As described in WO2005/012326, represented by chemical formula (13):

(14) Spiroketal derivatives of chemical formula (14):

Wherein R represents methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert-butyl;

(15) pyrazole-O-glucoside derivatives of chemical formula (15):

in

R ¹ represents C _1-3 -alkoxy,

L ¹ , L ² represent H or F independently of each other,

R ⁶ represents H, (C _1-3 -alkyl)carbonyl, (C _1-6 -alkyl)oxycarbonyl, phenoxycarbonyl, benzyl

Oxycarbonyl or benzylcarbonyl;

(16) Compounds of chemical formula (16):

(17) and Sergliflozin (Sergliflozin), represented by chemical formula (17):

The term "dapagliflozin" as used herein refers to dapagliflozin of the above structure and its pharmaceutically acceptable form, including its hydrate and solvate, and its crystal form. This compound and its method of synthesis are described, for example, in WO03/099836. Preferred hydrates, solvates and crystalline forms are described, for example, in patent applications WO2008/116179 and WO2008/002824.

The term "canagliflozin" as used herein refers to canagliflozin of the above structure and its pharmaceutically acceptable form, including its hydrate and solvate, and its crystal form. The compound and its synthesis are described, for example, in WO2005/012326 and WO2009/035969. Preferred hydrates, solvates and crystalline forms are described, for example, in patent application WO 2008/069327.

The term "empagliflozin" as used herein refers to empagliflozin of the above structure and its pharmaceutically acceptable form, including its hydrate and solvate, and its crystal form. The compound and its synthesis are described eg in WO2005/092877, WO2006/120208 and WO2011/039108. Preferred crystalline forms are described, for example, in patent applications WO2006/117359 and WO2011/039107.

The term "agliflozin" as used herein refers to the above-mentioned structure of apagliflozin and its pharmaceutically acceptable forms, including its hydrates and solvates, and its crystalline forms. This compound and its synthesis are described, for example, in WO2004/007517.

The term "Ipagliflozin" as used herein refers to Ipagliflozin of the above structure and its pharmaceutically acceptable forms, including its hydrates and solvates, and its crystalline forms. The compound and its synthesis are described, for example, in WO2004/080990, WO2005/012326 and WO2007/114475.

The term "topagliflozin" as used herein refers to topagliflozin of the above structure and its pharmaceutically acceptable form, including its hydrate and solvate, and its crystal form. The compound and its synthesis are described, for example, in WO2007/140191 and WO2008/013280.

The term "rupagliflozin" as used herein refers to rupagliflozin of the above structure and pharmaceutically acceptable forms thereof, including hydrates and solvates thereof, and crystalline forms thereof.

The term "epagliflozin" as used herein refers to the above-mentioned structure of epagliflozin and its pharmaceutically acceptable form, including its hydrate and solvate, and its crystal form. This compound is described eg in WO2010/023594.

The term "repagliflozin" as used herein refers to repagliflozin of the above structure and its pharmaceutically acceptable forms, including prodrugs of repagliflozin, especially repagliflozin etabonate, including its hydrates and solvates, and their crystalline forms. Their synthesis is described, for example, in patent applications EP1213296 and EP1354888.

The term "seragliflozin" as used herein refers to seragliflozin of the above-mentioned structure and its pharmaceutically acceptable forms, including prodrugs of seragliflozin, especially seragliflozin with carbonic acid, including its hydrates and solvates, and their crystalline forms. Its manufacture is described, for example, in patent applications EP1344780 and EP1489089.

Compounds of the above formula (16) and their manufacture are described, for example, in WO2008/042688 or WO2009/014970.

Preferred SGLT2 inhibitors are glucopyranosyl-substituted benzene derivatives. Optionally, one or more hydroxyl groups of such one or more SGLT2 inhibitors may be acylated with a group selected from: (C _1-18 -alkyl)carbonyl, (C _1-18 - Alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C _1-3 -alkyl)-carbonyl.

More preferred are the glucopyranosyl-substituted benzocyanide derivatives of formula (1) disclosed above. More preferred are glucopyranosyl-substituted benzyl cyanide derivatives of formula (18):

in

R ³ represents cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, 3-methyl- But-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethynyl , ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxy-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-propan-1 -yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl , 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxyl, difluoromethoxy, Trifluoromethoxy, 2-methoxy-ethoxy, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxygen or cyano (wherein ^R is preferably selected from cyclopropyl, ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran -3-yloxy or (S)-tetrahydrofuran-3-yloxy; and R3 is most preferably cyclopropyl,

or derivatives thereof, wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with a group selected from: (C _1-18 -alkyl)carbonyl, (C _1-18 -Alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C _1-3 -alkyl)-carbonyl.

Preferably, this SGLT2 inhibitor is 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranose-1-yl)-benzene, as shown in chemical formula (2) (also referred to herein as "Compound A"). Optionally, one or more hydroxyl groups of the β-D-glucopyranosyl group of Compound A are acylated with a group selected from: (C _1-18 -alkyl)carbonyl, (C _{1- 18} -Alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C _1-3 -alkyl)-carbonyl.

Thus, in a preferred embodiment, the SGLT2 inhibitor according to the invention is a glucopyranosyl-substituted benzene derivative SGLT2 inhibitor, preferably an SGLT2 inhibitor of formula (1), more preferably of formula (18), or More preferred are those of formula (2) (ie compound A), each instance as defined above.

metabolic disorder

The metabolic disorder can be diabetes, prediabetes, obesity, and/or any disorder, disease, sign or symptom associated with one or more of these disorders. In particular, the metabolic disorder may be hyperglycemia, insulin resistance, diabetes and/or hepatic lipidosis. Additional associated metabolic disorders include hyperinsulinemia, glucose intolerance, ketosis (especially ketoacidosis), hyperlipidemia, elevated blood adiposelin and/or glycerol levels, syndrome X (metabolic syndrome), Atherosclerosis, pancreatic inflammation, adipose tissue inflammation, and/or loss of pancreatic beta-cell function.

In some embodiments, the metabolic disorder is diabetes. Herein, diabetes may be pre-diabetes, type 1 diabetes or type 2 diabetes. In particular, diabetes may be type 2 diabetes. In some embodiments, diabetes can be associated with obesity.

In some embodiments, the metabolic disorder is hyperglycemia. As used herein, hyperglycemia may be associated with diabetes (eg, type 2 diabetes). In some embodiments, hyperglycemia can be associated with obesity. The hyperglycemia can be chronic.

In some embodiments, the metabolic disorder is insulin resistance. Insulin resistance in this context may be associated with diabetes, for example with type 2 diabetes. In some embodiments, insulin resistance can be associated with obesity.

In some embodiments, the metabolic disorder is glucose intolerance (IGT). In this context, glucose intolerance may be associated with diabetes, such as type 2 diabetes. In some embodiments, glucose intolerance can be associated with obesity.

In some embodiments, the metabolic disorder is hyperinsulinemia. In this context, hyperinsulinemia may be associated with diabetes, such as type 2 diabetes. In some embodiments, hyperinsulinemia can be associated with obesity.

In some embodiments, the metabolic disorder is one or more of hyperglycemia, insulin resistance, and hepatic lipidosis. In some embodiments, the metabolic disorder is selected from hyperglycemia and insulin resistance.

In some embodiments, the metabolic disorder is one or more of hyperinsulinemia, glucose intolerance, hyperglycemia, and insulin resistance.

In certain embodiments, the feline is obese. For example, one or more metabolic disorders selected from hyperglycemia, insulin resistance and hepatic lipidosis can be treated and/or prevented in obese felines according to the present invention. Additionally, for example, hyperinsulinemia and/or glucose intolerance can be treated and/or prevented in obese felines. Additionally, in obese felines it is possible to treat and/or prevent the group selected from the group consisting of ketosis (especially ketoacidosis), hyperlipidemia, elevated blood adiposelin and/or glycerol levels, Syndrome X (Metabolic Syndrome) Disorders of one or more of , atherosclerosis, pancreatic inflammation, adipose tissue inflammation, and loss of pancreatic beta cell function.

In certain embodiments, the feline has diabetes, such as type 2 diabetes. For example, one or more metabolic disorders selected from hyperglycemia, insulin resistance, and hepatic lipidosis can be treated and/or prevented in felines with diabetes (eg, type 2 diabetes) according to the present invention. Additionally, for example, hyperinsulinemia and/or glucose intolerance can be treated and/or prevented in felines with diabetes (eg, type 2 diabetes). In addition, in cats with diabetes (such as type 2 diabetes), it is possible to treat and/or prevent the group selected from ketosis (especially ketoacidosis), hyperlipidemia, elevated blood adipose and/or glycerol levels, Disorders of one or more of syndrome X (metabolic syndrome), atherosclerosis, inflammation of the pancreas, inflammation of adipose tissue, and loss of pancreatic beta cell function.

In some embodiments, the feline is obese and has diabetes (eg, type 2 diabetes). In some embodiments, the feline has diabetes (eg, type 2 diabetes) but is not obese. In some embodiments, the feline is obese but not diabetic.

The present invention also provides the use of one or more SGLT2 inhibitors, preferably Compound A, for treating and/or preventing degeneration of pancreatic β cells. For example by increasing the quality of pancreatic beta cells, and/or improving and/or restoring the functionality (ie insulin secretion) of pancreatic beta cells in felines.

Ketosis A state of elevated levels of ketone bodies in the body. Ketoacidosis can be described as a type of metabolic acidosis caused by high concentrations of ketone bodies (formed by the cleavage of fatty acids and deamination of amino acids). Two common ketones produced in humans are acetoacetate and beta-hydroxybutyrate. In cats, three ketones were found to predominate: acetoacetate, beta-hydroxybutyrate, and pyruvate. Ketoacidosis can be smelled on the subject's breath. This is due to acetone (a direct by-product of the natural breakdown of acetoacetate).

Ketoacidosis is an extreme and uncontrolled form of ketosis. Ketosis is also a normal response to long-term dieting. In ketoacidosis, the body fails to adequately regulate ketone production (particularly through the production of acetyl-CoA), causing such a severe accumulation of ketoacids that the blood pH is greatly reduced, that is, excess ketone bodies can significantly make Acidification of the blood. In extreme cases, ketoacidosis can be fatal.

Ketoacidosis can occur when the body produces high levels of ketone bodies (ketosis) through the metabolism of fatty acids and insulin does not adequately relieve their production (eg, due to insulin resistance/reduced insulin sensitivity). The development of high blood sugar levels (hyperglycemia) due to lack of insulin can lead to further acidification of the blood. This usually does not happen in healthy individuals because the pancreas produces insulin in response to elevated ketone/glucose levels.

Ketoacidosis is most common in untreated diabetes (when the liver breaks down fat and protein in response to a perceived need for respiratory substrates).

Prediabetes in felines is characterized by hyperinsulinemia, insulin resistance in target organs, glucose intolerance, including changes in insulin response eg to glycemic challenges, also eg induced by stress. Prediabetes is also often associated with obesity. Prediabetes can also be associated with intermittent hyperglycemia.

Type 2 diabetes in felines is characterized by decreased insulin production in target organs and insulin resistance. A decrease in insulin production may eg be caused by amyloid accumulation in β-cells, glucotoxicity and/or infection of the pancreas. Defects in β-cell function are usually progressive and lead to complete loss of insulin secretion in some felines. Genetic factors, sugar steroids, progesterone, lack of exercise, and obesity are possible causes of insulin resistance. For example, in healthy cats, insulin sensitivity decreases by 50% after >40% weight gain. Cats with diabetes are thought to be predominantly type 2, based on the fact that most cats with diabetes have islet amyloid, which is known to be a hallmark of type 2 diabetes.

It is thought that only a small minority of cats develop secondary forms of diabetes.

Clinical signs of diabetes observed in felines include polydipsia, polyuria, weight loss, and/or polyphagia. In cats, anorexia is more often described as hyperphagia. A characteristic sign of diabetes in cats is plantigrade stance (weakness of the hind legs, elbow touching the ground when the cat walks). This is caused by diabetic neuropathy.

In the context of the present invention, additional particularly relevant signs of diabetes in felines are hyperglycemia and glycosuria. Hyperglycemia in felines (eg cats) is defined as plasma glucose values above normal (3.9-8.3 mmol/l or 70-150 mg/dl), eg 8 mmol/l or more or 150 mg/dl or more of plasma glucose. Diabetes in felines (eg, cats) is defined as higher than normal levels of glucose in the urine (0-2 mmol/L, or 36 mg/dl). Glucose concentration The renal threshold is reached at a blood glucose concentration of approximately 11-17 mmol/l or 200 to 300 mg/dl.

The diagnosis of diabetes in felines can also be based on three conditions, for example, as follows:

(1) Blood glucose concentration measurement > 250mg/dl when dieting;

(2) Glycosuria as defined above; and

(3) One or more of the following: polyuria, polydipsia, polyphagia, weight loss despite a good appetite, or ketonuria (no signs of severe ketoacidosis).

In addition to and in support of the above diagnosis, further investigations may include hematology, blood chemistry, X-rays and/or abdominal ultrasound.

Preferably, the use according to the invention of said one or more SGLT2 inhibitors, preferably compound A, makes it possible to maintain and/or establish a normal or near normal glucose concentration. However, unlike human therapy, this is not believed to always be necessary in diabetic animals and thus not always the object of the present invention. According to the invention, the blood glucose concentration can also be maintained, for example, between 5.5 and 16.6 mmol/l or between 100 and 300 mg/dl. For felines it is often sufficient.

The goal of treating prediabetes or diabetes in felines according to the present invention may be to eliminate signs observed by the owner (e.g., lethargy, polyuria, polydipsia, weight loss) secondary to hyperglycemia in untreated animals. lighten, eat more, etc.). An additional therapeutic goal or therapeutic effect may be one or more of any of the advantageous effects of the invention disclosed herein, including, but not limited to, any one or more of: improved glucose tolerance, increased insulin sensitivity, reduced insulin resistance, improved glucose excursion in ivITT, improved insulin excursion in ivITT or oral glucose tolerance test (OGTT), decreased second phase insulin secretion, decreased body fat, body weight and/or blood leanness Lack of weight gain in the case of obese animals, reduced respiratory exchange rate (RER), and/or obese animals.

Diabetic remission may be used when normal (or near normal) blood glucose concentrations have been achieved, clinical signs have improved and insulin administration can be discontinued or has not been administered for at least 4 consecutive weeks. However, the viability of pancreatic beta cells may not have been fully restored. The use of one or more SGLT2 inhibitors, preferably Compound A, and thus reduced blood glucose concentrations, and improved insulin resistance and pancreatic beta cell function are believed to be critical to achieving and maintaining diabetic remission in felines .

Insulin resistance can be described as a condition in which normal amounts of insulin are insufficient to generate a normal insulin response from fat, muscle and liver cells. Insulin resistance in adipocytes reduces the effects of insulin and leads to increased hydrolysis of stored triglycerides (in the absence of measures to improve insulin sensitivity or provide additional insulin). Increased mobilization of stored lipids in these cells increases free fatty acids in plasma. Insulin resistance in muscle cells reduces glucose uptake (and thus local storage of glucose as glycogen), whereas insulin resistance in hepatocytes has impaired glycogen synthesis and fails to repress glucose production. Elevated blood fatty acid levels, decreased muscle glucose uptake, and increased hepatic glucose production all contribute to elevated blood glucose levels (hyperglycemia).

A surrogate index of insulin sensitivity can be calculated based on QUICKI (Quantitative Insulin Sensitivity Check Index: 1/log(glucose*insulin)) for basal blood levels. For dynamic testing, eg during a glucose challenge, a modified Belfiore index (1/log(ΔAUC-glucose*ΔAUC-insulin)) can be used.

Insulin resistance can arise in association with obesity, excess visceral fat, hypertension and dyslipidemia involving elevated triglycerides, small, dense low-density lipoprotein (sdLDL) particles, and decreased HDL cholesterol levels. For visceral adiposity, much evidence in humans suggests two strong associations with insulin resistance. First, unlike subcutaneous adipose tissue, visceral adipocytes produce significant amounts of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), and interleukin-1 and -6. These pro-inflammatory cytokines profoundly disrupt normal insulin action in fat and muscle cells in a number of experimental models and may be responsible for causing systemic insulin resistance as observed in human patients with excess visceral fat major factor. Similarly, excess fat accumulation in felines contributes to low-grade systemic inflammation. The cause of the vast majority of cases of insulin resistance remains unknown. Clearly there is a genetic component. However, there is some reason to suspect that insulin resistance is associated with a high carbohydrate diet. Inflammation also appears to be involved in causing insulin resistance.

Hyperinsulinemia can be described as a condition in which there are excess levels of circulating insulin in the blood, ie more than about 35 pmol/L below basal or about 200 pmol/L, for example during glycemic challenges (eg ivGTT or stress). As mentioned, it often arises in the context of (and may be a consequence of) insulin resistance in felines.

Glucose intolerance can be described as a condition in which glucose excursions and blood glucose spikes are more severe in response to a glycemic challenge, such as after a meal or after a stress test (glucose tolerance test) or after a stress-induced increase in blood glucose concentration. Prolonged periods of high and/or glucose fluctuations.

Dyslipidemia or hyperlipidemia is the presence of abnormal elevated levels of lipids and/or lipoproteins in the blood. Lipid and lipoprotein abnormalities are considered to be highly modifiable risk factors for cardiovascular disease (due to the influence of cholesterol). Glycerol is a precursor for the synthesis of triacylglycerols (triglycerides) and phospholipids in the liver and adipose tissue. When the body uses fat as an energy source, glycerol and fatty acids are released into the bloodstream after triglycerides are hydrolyzed. The glycerol component can be converted by the liver into glucose and provides energy for cellular metabolism. Normal levels of free fatty acids in the blood of companion (eg, feline) animals are triglyceride concentrations of 50 to 100 mg/dl (0.6 to 1.2 mmol/l). For cats, normal levels of blood cholesterol are, for example, 70-150 mg/dl.

Abnormal alipin can be described as a condition in which circulating plasma levels of biologically active substances produced in adipose tissue (acting in an autocrine/paracrine or endocrine manner) are altered. For example an increase in leptin and/or a decrease in adiponectin.

Subclinical or systemic inflammation, especially low-grade systemic inflammation characterized by increased expression and secretion of pro-inflammatory cytokines such as tumor necrosis factor-α and/or anti-inflammatory cytokines such as interleukin-10 and/or its Decreased body-marked and secreted levels of the respective heads.

Obesity can be described as the medical condition in which excess body fat, accumulated to such an extent that it can have adverse health effects, results in shortened lifespan. In obese felines, for example body condition scores (BCS) above 6 (up to 9) are encountered.

Metabolic disorders to be treated and/or prevented according to the invention include syndrome X (metabolic syndrome). This disorder can be described as a combination of medical disorders that increase the risk of developing cardiovascular disease and diabetes. Metabolic syndrome is also known as metabolic syndrome X (metabolic syndrome), syndrome X (metabolic syndrome), insulin resistance syndrome, Reaven's syndrome, and CHAOS (coronary artery disease, hypertension, atherosclerosis, Abbreviation for obesity, and shock).

The exact mechanisms underlying the complex pathways of metabolic syndrome are not fully understood. The pathophysiology is extremely complex and only partially elucidated. Most patients are older, obese, sedentary, and have some degree of insulin resistance. The most important factors are, in order: (1) overweight and obesity, (2) genetics, (3) age, and (4) a sedentary lifestyle, ie, low activity and excess calorie intake.

An additional risk factor is diabetes. At least in humans, the majority (-75%) of patients with type 2 diabetes or glucose intolerance (IGT) have metabolic syndrome.

The pathophysiology is usually characterized by visceral fat, after which adipocytes (adipocytes) of visceral fat increase plasma levels of TNF-alpha and alter levels of many others (eg, adiponectin, resistin, PAI-1) . It has been shown that TNF-α not only causes the production of inflammatory cytokines, but also induces cellular signaling, possibly through interaction with TNF-α receptors, which can lead to insulin resistance.

The current first line of treatment is lifestyle modification (ie, calorie and physical activity restriction). However, drug treatment is often required. Individual disorders contributing to the metabolic syndrome can be treated individually. Diuretics and ACE inhibitors can be used to treat high blood pressure. Cholesterol medications can be used to lower LDL cholesterol and triglyceride levels (if they are raised) and to raise HDL levels (if they are low). Such treatment may be combined with the use of one or more SGLT2 inhibitors, preferably Compound A, according to the invention.

Metabolic disorders to be treated and/or prevented according to the invention include inflammation of the pancreas (pancreatitis). Such disorders can occur in acute or chronic form. Chronic pancreatitis may occur with or without steatorrhea and/or diabetes.

Pancreatitis can be caused by: hypertriglyceridemia (especially when triglyceride values exceed 1500 mg/dl (16 mmol/l)), hypercalcemia, viral infection, trauma, vasculitis (i.e. small vascular inflammation), and autoimmune pancreatitis.

Metabolic disturbances, in particular dyslipidemia and elevated serum levels of triglycerides are risk factors for developing pancreatitis and can thus be treated in combination with pancreatitis according to the invention. Therefore, the present invention also provides prevention of pancreatitis. Therefore, the present invention also provides prevention of pancreatitis.

Metabolic disorders to be treated and/or prevented according to the invention include inflammation of adipose tissue (panniculitis), which is a group of disorders characterized by inflammation of subcutaneous adipose tissue.

Panniculitis can occur in adipose tissue (cutaneous and/or visceral). It can be diagnosed on the basis of deep skin biopsy and can be further classified by histological features based on the location of inflammatory cells (within the fat lobules or in the septum separating them) and based on the presence or absence of vasculitis. Panniculitis can also be classified based on the presence or absence of systemic symptoms.

Metabolic diseases, especially pancreatitis, are risk factors for developing panniculitis and can thus be treated in combination with panniculitis according to the invention. Accordingly, the present invention also provides prevention of panniculitis.

Cats

As used herein, a feline is a member of the family Felidae (ie, felid). It may thus belong to either the Felinae or Pantherinae subfamily. The term feline encompasses the term cat, eg, domestic cat. The term domestic cat encompasses the terms domestic cat (Feliscatus) and domestic cat (Felissilvestriscatus).

pharmaceutically acceptable form

Herein, references to the SGLT2 inhibitors of the present invention and/or their uses encompass pharmaceutically acceptable forms of said SGLT2 inhibitors, unless otherwise stated.

According to the present invention, any pharmaceutically acceptable form of said SGLT2 inhibitor can be used, such as formula (1), preferably formula (18), more preferably formula (2). For example crystalline forms may be used. Prodrug forms are also contemplated by the present invention.

Prodrug forms may include, for example, esters and/or hydrates. The term prodrug is also meant to include any valence-binding carrier that releases the active compound of the invention in vivo when the prodrug is administered to a mammalian subject. Prodrugs of the compounds of the invention can be prepared by modifying functional groups of the compounds of the invention in such a way that the cleavage modification (either by routine manipulation or in vivo) becomes the parent compound of the invention.

Crystalline forms useful in the present invention include complexes of a SGLT2 inhibitor with one or more amino acids (see eg WO2014/016381). Amino acids used for this purpose may be natural amino acids. The amino acids may be proteinogenic amino acids (including L-hydroxyproline), or non-proteinogenic amino acids. The amino acids may be D- or L-amino acids. In some preferred embodiments, the amino acid is proline (L-proline and/or D-proline, preferably L-proline). For example, 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranose-1-yl)-benzene (chemical formula (2); compound A) and proline Crystalline complexes of acids such as L-proline.

Thus, the present invention discloses crystalline complexes between one or more natural amino acids and SGLT2 inhibitors, e.g., crystalline complexes of one or more natural amino acids and glucopyranosyl-substituted benzene derivatives SGLT2 inhibitors (preferably A crystalline complex between formula (1), more preferably formula (18) or more preferably formula (2) (SGLT2 inhibitor of compound A). Thus, disclosed herein is the combination of one or more natural amino acids with 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranose-1-yl)-benzene (compound A ) between crystalline complexes.

Also disclosed herein is the use of one or more crystalline complexes as defined herein above or below for the manufacture of a pharmaceutical composition suitable for the treatment and/or prophylaxis of a disease or condition, said disease or Symptoms can be affected by inhibiting the sodium-dependent glucose cotransporter SGLT, preferably SGLT2. Also disclosed herein is the use of one or more crystalline complexes as defined herein above or below for the manufacture of a pharmaceutical composition for inhibiting the sodium-dependent glucose cotransporter SGLT2.

A crystalline complex between one or more natural amino acids (eg proline, preferably L-proline) and an SGLT2 inhibitor is a preferred pharmaceutically acceptable form of an SGLT2 inhibitor for use according to the invention. Specifically, one or more natural amino acids (such as proline, preferably L-proline) and glucopyranosyl-substituted benzene derivative SGLT2 inhibitors (preferred SGLT2 inhibitors of chemical formula (1), more preferably Crystalline complexes of formula (18), more preferably formula (2) (compound A)), are preferred pharmaceutically acceptable forms of SGLT2 inhibitors for use according to the invention. One or more natural amino acids (such as proline, preferably L-proline) and 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranose-1 The crystalline complex between -yl)-benzene (compound A) is a particularly preferred pharmaceutically acceptable form of the SGLT2 inhibitor for use according to the invention.

Also disclosed herein is a method for the preparation of one or more crystalline complexes as defined herein above or below, said method comprising the steps of:

(a) prepare said SGLT2 inhibitor (such as glucopyranosyl-substituted benzene derivatives, or chemical formula (1), preferably chemical formula (18) or more preferably chemical formula (2) i.e. compound in solvent or solvent mixture A solution of the SGLT2 inhibitor of A) and one or more natural amino acids;

(b) storing said solution to precipitate the crystalline complex from solution;

(c) removing the precipitate from said solution; and

(d) optionally drying the precipitate until any excess of the solvent or solvent mixture is removed.

A certain pharmaceutical activity is the basic prerequisite for a pharmaceutical active substance to be approved as a drug on the market. However, pharmaceutically active substances have many other requirements to be fulfilled. These requirements are based on various parameters linked to the properties of the active substance itself. Without limitation, examples of such parameters are the stability of the active substance under various environmental conditions, its stability during the production of pharmaceutical formulations and the stability of the active substance in the final pharmaceutical composition. The pharmaceutically active substances used for the preparation of pharmaceutical compositions should be as pure as possible and their long-term storage stability under various environmental conditions must be guaranteed. This is important to prevent the use of pharmaceutical compositions which contain, for example, decomposition products thereof in addition to the actual active substance. In such cases, the drug may contain less active substance than advertised.

Uniform distribution of the drug in the formulation is a critical factor, especially when the drug must be given in low doses. In order to ensure a uniform distribution, the particle size of the active substance can be reduced to a suitable level, for example by milling. Since the decomposition of the pharmaceutical active substance as a side effect of milling (or micronization) needs to be avoided as much as possible, the active substance must be highly stable throughout the milling process, although the conditions required in this process are severe. It is only possible to produce homogeneous pharmaceutical preparations (which always contain the specified amount of active substance) in a reproducible manner if the active substance is sufficiently stable during milling.

A further problem that may arise during milling for the preparation of the desired pharmaceutical formulation is the energy input and stress on the crystal surface that this process may cause. This can in some cases lead to polymorphic amorphization, or to a change in the crystal lattice. The stability and properties of crystalline active substances are also subject to stringent requirements in this regard, since the drug dosage of pharmaceutical preparations requires that the active substance always have the same crystalline form.

The stability of pharmaceutical actives in pharmaceutical compositions is also important in determining the shelf life of a particular drug; shelf life is the length of time during which a drug can be administered without any risk. The high stability of the drug in the aforementioned pharmaceutical composition under various storage conditions is thus an additional advantage for both the patient and the manufacturer.

Moisture absorption reduces the content of pharmaceutically active substances due to weight gain caused by water intake. Pharmaceutical compositions that have a tendency to absorb moisture need to be protected from moisture during storage, for example by adding suitable desiccants or by storing the drug in a moisture-proof environment. Thus, preferably the pharmaceutical active should be somewhat hygroscopic.

In addition, the well-defined crystalline form enables the purification of drug substances by recrystallization.

In addition to the above requirements, it should be remembered that any modification to the solid state of a pharmaceutical composition that improves its physical and chemical stability is a significant advantage over less stable forms of the same drug.

Between natural amino acids and SGLT2 inhibitors (such as glucopyranosyl-substituted benzene derivatives, or chemical formula (1), or chemical formula (18), or especially chemical formula (2), that is, the SGLT2 inhibitor of compound A) The crystalline composite fulfills the important requirements mentioned above.

Preferably the natural amino acid exists in its (D) or (L) enantiomer, most preferably as the (L) enantiomer.

Also those crystalline complexes according to the present invention are preferably formed between said SGLT2 inhibitor (e.g. formula (1), preferably formula (18), or especially formula (2), ie compound A) and a natural amino acid Most preferably, it is formed between compound A and the (L) enantiomer of a natural amino acid.

Preferred amino acids according to the invention are selected from: phenylalanine and proline, in particular (L)-proline and (L)-phenylalanine.

The crystalline complex according to a preferred embodiment is characterized in that the natural amino acid is proline, in particular (L)-proline.

Preferably the molar ratio between the SGLT2 inhibitor (e.g. formula (1), preferably formula (18), or especially formula (2), i.e. compound A) and natural amino acid ranges from about 2:1 to about 1:3 ; more preferably from about 1.5:1 to about 1:1.5, more preferably from about 1.2:1 to about 1:1.2, most preferably about 1:1. Such an embodiment is referred to hereinafter as "complex (1:1)" or "1:1 complex".

A preferred crystalline complex according to the present invention is therefore a complex between said SGLT2 inhibitor (e.g. formula (1), preferably formula (18), or especially formula (2), ie compound A) and proline ( 1:1); especially between the SGLT2 inhibitor and L-proline.

According to a preferred embodiment, said crystalline complex, in particular said 1:1 complex of the SGLT2 inhibitor with L-proline, is a hydrate.

Preferably the molar ratio of crystalline complex to water ranges from about 1:0 to 1:3; more preferably from about 1:0 to 1:2, more preferably from about 1:0.5 to 1:1.5, most preferably about 1:0.8 to 1:1.2, especially around 1:1.

The crystalline complex of the SGLT2 inhibitor with proline (particularly L-proline) and water can be identified and distinguished from other crystalline forms by means of its characteristic X-ray powder diffraction (XRPD) pattern.

For example, a crystalline complex of Compound A with L-proline is preferably characterized by an X-ray powder diffraction pattern comprising peaks at 20.28, 21.14, and 21.64 degrees 2Θ (±0.1 degrees 2Θ), wherein X-ray powder diffraction patterns were prepared with CuKα1 rays.

In particular said X-ray powder diffraction pattern comprises peaks at 4.99, 20.28, 21.14, 21.64 and 23.23 degrees 2Θ (±0.1 degrees 2Θ), wherein said X-ray powder diffraction pattern was prepared with CuKα1 radiation.

More specifically, the X-ray powder diffraction pattern comprises peaks at 4.99, 17.61, 17.77, 20.28, 21.14, 21.64, 23.23, and 27.66 degrees 2Θ (±0.1 degrees 2Θ), wherein the X-ray powder diffraction pattern Prepared with CuKα1 rays.

More specifically, the X-ray powder diffraction pattern comprises peaks at 4.99, 15.12, 17.61, 17.77, 18.17, 20.28, 21.14, 21.64, 23.23, and 27.66 degrees 2Θ (±0.1 degrees 2Θ), wherein the X The X-ray powder diffraction pattern was prepared with CuKα1 radiation.

More specifically, the crystalline complex of Compound A with L-proline is characterized by an X-ray powder diffraction pattern prepared using CuKα1 radiation, which contains peak.

Table 1: X-ray powder diffraction pattern of the crystalline complex of compound A and L-proline (only the peaks up to 30° in 2Θ are listed):

More specifically, the crystalline complex was characterized by an X-ray powder diffraction pattern prepared using CuKα1 radiation, which contained peaks at degrees 2Θ (±0.1 degrees of 2Θ, as shown in Figure 11).

In addition, said crystalline complex of Compound A with L-proline is characterized by a melting point in excess of 89°C, particularly in the range from about 89°C to about 115°C, more preferably in the range from about 89°C to about 110°C (by DSC Determined; assessed as onset temperature; heating rate 10K/min). This crystalline complex can be observed to melt upon dehydration. The obtained DSC curve is shown in FIG. 12 .

The crystalline complex of Compound A with L-proline showed weight loss by thermogravimetric analysis (TG). The observed weight loss indicates that the crystalline form contains moisture (which may be bound by adsorption and/or which may be part of the crystal lattice), ie the crystalline form may exist as a crystal hydrate. The moisture content in the crystalline form ranges from 0 to about 10 wt-%, especially from 0 to about 5 wt-%, more preferably from 1.5 to about 5 wt-%. The dashed line in Figure 2 shows the moisture weight loss between 2.8 and 3.8%. The stoichiometry close to the monohydrate can be estimated from the observed weight loss.

The crystalline complex has excellent physicochemical properties, which are advantageous in the preparation of pharmaceutical compositions. Especially crystalline complexes have a high degree of physical and chemical stability under various environmental conditions and during the production of pharmaceuticals. For example, crystals can be obtained in a shape and particle size which are particularly suitable for the production process of solid pharmaceutical formulations. In addition, the crystals exhibit a high degree of mechanical stability allowing grinding of the crystals. In addition, the crystalline complexes do not show a high tendency to absorb moisture and are chemically stable, ie the crystalline complexes allow the production of solid drugs with a long shelf life. On the other hand, the crystalline complex is highly soluble over a broad pH range, which is advantageous for solid pharmaceutical formulations for oral administration.

X-ray powder diffraction patterns can be recorded using a STOE-STADIP-diffractometer in emission mode, equipped with an unknown inductive detector (OED) and a Cu-anode as X-source (CuKα1 rays, 40kV, 40mA). The value "2Θ[°]" in Table 1 represents the angle of diffraction expressed in degrees, while the value on behalf of The specified distance between the lattice planes represented. The intensities shown in Figure 11 are given in units of cps (counts per second).

In order to allow for experimental errors, the 2Θ values stated above should be understood precisely as ±0.1 degrees 2Θ, in particular ±0.05 degrees 2Θ. That is to say, when evaluating whether a given crystal sample of Compound A is a crystalline form according to the above-mentioned 2Θ value, if the experimentally observed 2Θ value of the sample falls within ±0.1 degrees of the above-mentioned characteristic value ( Especially within 2Θ of ±0.05 degrees), it should be considered equal to the characteristic value.

Melting points were determined by DSC (Differential Scanning Calorimetry) using a DSC821 (Mettler Toledo). Weight loss was determined by thermogravimetric analysis (TG) using TGA851 (Mettler Toledo).

Also disclosed herein is a method for preparing the crystalline complex as defined above and below, said method comprising the steps of:

(a) preparing a solution of an SGLT2 inhibitor as described herein (e.g., Compound A or any other SGLT2 inhibitor described herein) and one or more natural amino acids in a solvent or mixture of solvents;

(b) storing said solution to precipitate the crystalline complex from solution;

(c) removing the precipitate from said solution; and

(d) optionally drying the precipitate until any excess of the solvent or solvent mixture is removed.

According to step (a), a solution of said SGLT2 inhibitor (eg Compound A or any other SGLT2 inhibitor described herein) and said one or more natural amino acids in a solvent or solvent mixture is prepared. For the crystalline complex, it is preferred that the solution is saturated or at least close to saturated or even supersaturated. In step (a), the SGLT2 inhibitor may be dissolved in a solution comprising the one or more natural amino acids, or the one or more natural amino acids may be dissolved in a solution comprising the SGLT2 inhibitor middle. According to an additional procedure, dissolving the SGLT2 inhibitor in a solvent or mixture of solvents to produce a first solution and dissolving the one or more natural amino acids in a solvent or mixture of solvents to produce a second solution Second solution. Said first solution and said second solution are then combined to form a solution according to step (a).

Preferably the molar ratio of natural amino acid to said SGLT2 inhibitor (eg compound A or any other SGLT2 inhibitor described herein) in solution corresponds to the molar ratio of natural amino acid to said SGLT2 inhibitor in the crystalline complex to be obtained. Preferred molar ratios therefore range from about 1:2 to 3:1; most preferably about 1:1.

Suitable solvents are preferably selected from: C _1-4 -alcohols, water, ethyl acetate, acetonitrile, acetone, diethyl ether, tetrahydrofuran, and mixtures of two or more of these solvents.

More preferred solvents are selected from methanol, ethanol, isopropanol, water, and mixtures of two or more of these solvents, especially mixtures of one or more of said organic solvents with water.

Particularly preferred solvents are selected from the group consisting of ethanol, isopropanol, water and mixtures of ethanol and/or isopropanol with water.

In the case of using a mixture of water and one or more C _1-4 -alcohols (in particular methanol, ethanol and/or isopropanol, most preferably ethanol), the preferred volume ratio of water:alkanol ranges from about 99: 1 to 1:99; more preferably from about 50:1 to 1:80; more preferably from about 10:1 to 1:60.

Preferably said step (a) is carried out at about room temperature (about 20° C.), or at elevated room temperature (up to about the boiling point of the solvent or solvent mixture used).

According to a preferred embodiment, said SGLT2 inhibitor (such as Compound A or any other SGLT2 inhibitor described herein) and/or said one or more natural amino acids and/or said solvent and solvent mixture The starting material contains an amount of _H2O which is at least the amount required to form a hydrate of said SGLT2 inhibitor; in particular at least 1 mol, preferably at least 1.5 mol of water per mole of SGLT2 inhibitor. More preferably the amount of water is at least 2 mol of water per mole of SGLT2 inhibitor. This means that said SGLT2 inhibitor (such as compound A) as starting material, or said one or more natural amino acids, or said solvent or solvent mixture, or said compound and/or solvent combination contains the above The stated amount of H ₂ O. For example, in step (a), if the SGLT2 inhibitor (such as compound A) or the starting material of the natural amino acid does contain sufficient moisture as specified above, the moisture in the solvent is not necessary.

In order to reduce the solubility of the crystalline complex according to the invention in solution, in step (a) and/or in step (b), one or more antisolvents may be added, preferably in step (a) during or at least at the beginning of step (b). Water is an example of a suitable antisolvent. The amount of antisolvent is preferably selected so as to obtain a supersaturated or saturated solution of the crystalline complex.

In step (b), the solution is stored for a time sufficient to obtain a precipitate (ie crystalline complex). The temperature of the solution in step (b) is about the same or lower than that in step (a). During storage, the temperature of the solution is preferably reduced, preferably to a range of 20°C to 0°C or even lower. Step (b) may be performed with or without agitation. By varying the time period and temperature in step (b), the size, shape and quality of the crystals obtained can be controlled, as known to those skilled in the art. Additionally, crystallization may be induced by methods known in the art, such as by mechanical means such as scraping or wiping the contact surfaces of the reaction vessel using, for example, a glass rod. Optionally the (nearly) saturated or supersaturated solution can be seeded with seed crystals.

In step (c), the solvent can be removed from the precipitate by known methods, such as, for example, filtration, suction filtration, decantation or centrifugation.

In step (d), excess solvent is removed from the precipitate by methods known to those skilled in the art, such as for example by reducing the partial pressure of the solvent (preferably in vacuum), and/or by raising the temperature above about 20° C., preferably In the temperature range below 100°C, more preferably below 85°C.

Compound A can be synthesized by the methods specifically and/or fully described or cited in International Application WO2007/128749, which is incorporated herein by reference in its entirety, and/or by the methods disclosed in the Examples hereinafter. The biological properties of compound A can also be investigated as described in WO2007/128749.

The crystalline complexes described herein are preferably used as pharmaceutically active substances in substantially pure form, that is to say substantially free of other crystalline forms of the SGLT2 inhibitor (eg Compound A). Nevertheless, the present invention also includes crystalline complexes mixed with other crystalline forms or multiple crystalline forms. If the pharmaceutically active substance is a mixture of crystalline forms, it is preferred that the substance comprises at least 50% by weight, more preferably at least 90% by weight, most preferably at least 95% by weight of the crystalline complex described herein.

In view of its ability to inhibit SGLT activity, the crystalline complexes according to the invention are suitable for use in the treatment and/or prophylaxis of conditions or diseases which can be inhibited by SGLT activity, in particular SGLT-2 activity effects, especially metabolic disorders as described herein. The crystalline complexes according to the invention are also suitable for the preparation of pharmaceutical compositions for the treatment and/or prophylaxis of conditions or diseases which may be affected by inhibition of SGLT activity, in particular SGLT-2 activity, in particular is a metabolic disorder as described herein. The crystalline complexes as described herein, in particular of Compound A with natural amino acids such as proline, especially L-proline, are also suitable for use in the treatment of felines.

Pharmaceutical Compositions and Formulations

The SGLT2 inhibitors for use in the present invention can be prepared as pharmaceutical compositions. They can be prepared as solid or liquid formulations. In each case, they are preferably prepared for oral administration, preferably in liquid form. However, the SGLT2 inhibitors may also be prepared for, eg, parenteral administration.

Solid preparations include tablets, granular forms, and other solid forms such as suppositories. Among solid preparations, tablet and granule forms are preferred.

A pharmaceutical composition within the meaning of the invention may comprise an SGLT2 inhibitor according to the invention together with one or more excipients. Any excipient that permits, or supports, the desired medical effect can be used. Such excipients are available to those skilled in the art. Usable excipients are, for example, antiadherents (for reducing the adhesion between the powder (granules) and the punching interface, and thus preventing the punching from sticking to the tablet), binders (to bind the components solution binders or dry binders together), coatings (to protect tablet components from moisture in the air and to make large or bad-tasting tablets easier to swallow), disintegrants ( to allow the tablet to disintegrate after dilution), fillers, diluents, flavorings, pigments, glidants (flow regulators - facilitate powder flow by reducing interparticle friction and agglomeration), lubricants (to prevent agglomeration of components together and adhered to tablet punching or capsule filling machines), preservatives, adsorbents, sweeteners, etc.

A formulation according to the invention, such as a solid formulation, may comprise a carrier and/or a disintegrant selected from the group consisting of sugars and sugar alcohols, such as mannitol, lactose, starch, cellulose, microcrystalline cellulose and cellulose derivatives, For example methyl cellulose etc.

Procedures for the preparation of formulations suitable for felines are known to those skilled in the art and include, for solid formulations, for example direct compression, dry granulation and wet granulation. In the direct compression process, the active ingredient is placed together with all other excipients in a compression device which is used directly to extrude a tablet from this material. The resulting tablets may optionally be subsequently coated for physical and/or chemical protection thereof, for example with materials known in the art.

A unit for administration (e.g. a single liquid dose or a solid formulation unit such as a tablet) may contain from 0.1 mg to 10 mg, or such as from 0.3 mg to 1 mg, from 1 mg to 3 mg, from 3 mg to 10 mg; or from 5 to 2500 mg, or such as from 5 to 2000 mg , 5 mg to 1500 mg, 10 mg to 1500 mg, 10 mg to 1000 mg, or 10-500 mg of an SGLT2 inhibitor for use in the present invention. As will be appreciated by those skilled in the art, the amount of the SGLT2 inhibitor in the solid formulation for administration to a feline, or any formulation disclosed herein, may be increased or decreased to correspond to the body weight of the feline to be treated. into an appropriate ratio.

In one embodiment the pharmaceutical composition for use according to the invention is designed for oral or parenteral administration, preferably for oral administration. In particular oral administration can be modified by excipients which modify the odor and/or tactile properties of the pharmaceutical composition for the patient, eg as described.

When the SGLT2 inhibitor for use according to the invention is formulated for oral administration, it is preferred that the excipient confers properties such as palatability and/or chewability making the formulation suitable for administration to felines.

Liquid formulations are also preferred. Liquid preparations may be, for example, solutions, slurries or suspensions. They may be administered directly to the feline, or may be mixed with the feline's food and/or drink (eg, drinking water, etc.). One advantage of liquid formulations (similar to formulations in granular form) is that this form of administration allows precise dosing. For example, the SGLT2 inhibitor can be administered in a precise proportion to the body weight of the feline. The usual ingredients of liquid formulations are known to those skilled in the art.

Dosage and Administration

Suitable dosages for use in the present invention can be determined by those skilled in the art. Preferred unit dosage units include mg/kg, ie mg SGLT2 inhibitor per kg body weight of the feline. The SGLT2 inhibitors of the invention may, for example, be administered at a dose of 0.01-5 mg/kg per day, such as 0.01-4 mg/kg, such as 0.01-3 mg/kg, such as 0.01-2 mg/kg, such as 0.01-1.5 mg/kg, such as 0.01-1 mg/kg, such as 0.01-0.75 mg/kg, such as 0.01-0.5 mg/kg, such as 0.01-0.4 mg/kg, such as 0.01-0.4 mg/kg per day; or 0.1 to 3.0 mg/kg per day, preferably per day 0.2 to 2.0 mg/kg, more preferably 0.1 to 1 mg/kg per day. In another preferred embodiment, the dosage is 0.02-0.5 mg/kg per day, more preferably 0.03-0.4 mg/kg per day, eg 0.03-0.3 mg/kg per day.

Those skilled in the art are able to prepare the SGLT2 inhibitors of the present invention for administration according to the desired dosage.

Preferably, according to the invention, the SGLT2 inhibitor is administered no more than three times a day, more preferably no more than twice a day, most preferably only once a day. The frequency of administration can be adjusted to the usual feeding rate of the feline.

According to the invention, the SGLT2 inhibitor is administered such that an appropriate plasma concentration (e.g. maximal plasma concentration, or plasma concentration after a given time, e.g. 4, 8, 12 or 24 hours after oral administration, preferably oral administration) of said SGLT2 inhibitor is achieved. about 8 hours later). For example, for Compound A, the plasma concentration (eg, the maximum plasma concentration, or the plasma concentration after the given time of oral administration) may be in the range of 2 to 4000 nM, such as 20 to 3000, or such as 40 to 2000 nM.

Preferably, this level is maintained in the blood for a period of at least 12 hours, more preferably at least 18 hours, most preferably at least 24 hours following administration and the time required for the SGLT2 inhibitor to reach the bloodstream.

Preferably, according to the present invention, the SGLT2 inhibitor is administered orally in liquid or solid form. The SGLT2 inhibitor can be administered directly into the animal's mouth (e.g. using a syringe, preferably a graduated syringe) or with the animal's diet (e.g. with its drinking water etc.), preferably in each case as a liquid form. However, the SGLT2 inhibitor can also be administered, eg parenterally, or by any other route, eg rectally.

The SGLT2 inhibitor can be used alone or in combination with other drugs. In some embodiments, one or more SGLT2 inhibitors, preferably Compound A, are used in combination with one or more other oral antihyperglycemic agents. When the SGLT2 inhibitor is used in combination with other drugs, the SGLT2 inhibitor and any other drug may be administered simultaneously, sequentially (in any order), and/or according to a chronologically staggered dosing regimen. In such embodiments, when the other drug for administration in combination with the SGLT2 inhibitor is not administered simultaneously with the SGLT2 inhibitor, the SGLT2 inhibitor and any other drug are preferably administered within at least 2 weeks, 1 month, 2 Months, 4 months, 6 months or longer (eg, 12 months), or a longer period of time.

In some embodiments, the SGLT2 inhibitor (alone or in combination with another agent) does not interact with 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7- (2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthine or a pharmaceutically acceptable salt thereof is used in combination, that is, cats are not treated with said compound family animals. In some embodiments, the SGLT2 inhibitor is not used in combination with a DPP-IV inhibitor, ie, the feline is not treated with a DPP-IV inhibitor.

In some embodiments, the SGLT2 inhibitor is used as monotherapy, that is, independent therapy, that is, no other drug is administered to the feline for the treatment or prevention of the same metabolic disorder, that is, the SGLT2 inhibitor. The metabolic disorder for which it is administered. For example, no other drug is administered to the feline for the treatment or prevention of the same metabolic disorder for a period of at least 2, 3, or 4 weeks before or after administration of the SGLT2 inhibitor.

Brief description of the drawings

Figure 1 : shows the correlation between plasma levels of Compound A and urinary glucose excretion (gluc/crea) normalized for creatinine. have a clear log-linear relationship.

Figure 2: shows normal lean cats (ivGTT [1 g/kg]) and insulin resistant obese cats according to Hoenig's (Mol Cell Endocrinol 2002, 197(1-2):221-229) in the intravenous glucose tolerance test (ivGTT) Blood glucose and insulin secretion profiles of cats before treatment with compound A (dashed line - before test, "before") and after 4 weeks of treatment with compound A (solid line). The enhanced and prolonged second phase of the insulin resistant obese cats used in this study was significantly improved by Compound A treatment.

Figure 3: Plot showing blood insulin and surrogate insulin sensitivity index (blood insulin-to-glucose relationship expressed by the modified Belfiore index) during an intravenous glucose tolerance test (ivGTT) in insulin resistant cats Area under (AUC) values, where are before ("Before") and after 4 weeks of treatment ("After") treatment with Compound A or its vehicle ("Control"), respectively. Treatment with compound A resulted in a significant reduction in insulin AUC (panel A), and a significant improvement in insulin sensitivity (panel B).

Figure 4: Shows the time course of blood glucose concentration [mmol/L] after insulin challenge during the intravenous insulin tolerance test (ivITT) in insulin-resistant cats treated with Compound A or its vehicle ("Control", respectively). ”) before treatment (dashed line – before test, “before”) and after 4 weeks of treatment (solid line). In untreated animals (controls), insulin sensitivity (IS) decreased throughout the study (Panel A). In comparison, treatment with compound A was associated with a significant improvement in IS (panel B).

Figure 5: Shows the time course of blood non-esterified fatty acid (NEFA) levels [mEq/L] after insulin challenge during ivITT in insulin-resistant cats treated with Compound A or its vehicle ("Control", respectively). ”) before treatment (dashed line – before test, “before”) and after 4 weeks of treatment (solid line). In untreated animals (control), NEFA elimination was significantly worsened over the study period (panel A), whereas treatment with Compound A significantly improved it (panel B).

Figure 6: shows a significant decrease in blood leptin concentration during treatment in treated cats.

Figure 7: shows a reduction in respiratory exchange rate (RER) (indicating increased lipid utilization) measured by indirect calorimetry in treated animals.

Figure 8: shows that β-hydroxybutyric acid levels (β-HB/BHB) in blood increased after 4 weeks of treatment with compound A.

Figure 9: shows the positive correlation between changes in blood leptin concentration and changes in RER before and after 4 weeks of treatment with compound A or vehicle (control).

Figure 10: shows the inverse correlation between blood β-hydroxybutyrate levels (β-HB/BHB) and RER after 4 weeks of treatment with compound A.

Figure 11 : X-ray powder diffraction pattern showing a representative batch of the crystalline complex of Compound A with L-proline (1:1).

Figure 12: DSC/TG plot showing a representative batch of the crystalline complex of Compound A with L-proline (1:1).

Figure 13: Mean blood glucose from the 9-hour glucose curve showing the day of visit.

Figure 14: Shows serum fructosamine on day of visit.

Figure 15: Preliminary data from 4 cats demonstrating a reduction in fasting insulin concentrations on day 7 compared to day -1 compared to a simultaneous decrease in mean glucose values (from 9 hour blood glucose curve). Insulin concentrations later reached a plateau, which could be explained by glucose concentrations that were already close to normalization. This reflects the normal physiological state in dieted animals: when glucose is within the normal range (the fasted state), an increase in insulin concentration is no longer expected. This preliminary data on fasting insulin values from 4 cats supports the claimed indication of "loss of pancreatic beta cell function" and "remission of metabolic disturbances, preferably insulin remission" as it demonstrates an increase in insulin concentration and a regression of glucose concentration and thus reflect a return to normal physiological responses.

Example

The following examples demonstrate the beneficial therapeutic effect on glycemic control and/or insulin resistance etc. in feline animals using one or more SGLT2 inhibitors according to the present invention. These examples are intended to illustrate the invention in more detail and are not intended to limit the scope of the claims.

Example 1: Pharmacokinetics (PK)/Pharmacokinetics (PD) of Compound A Single Oral Dosing in Cats

Compound A was administered to cats that were fasted overnight. Each group (n=3 per group) received a single oral administration of: vehicle (water) alone, or containing the SGLT2 inhibitor Compound A (doses of 0.01 mg/kg, 0.1 mg/kg and 1 mg/kg ) carrier. PK/PD testing was performed up to day 4 after a single administration of Compound A or its vehicle.

Table 2: Pharmacokinetic data, single dose (0.01/0.1/1.0 mg/kg)

parameter 0.01mg/kg 0.1mg/kg 1.0mg/kg t _max [hours] average 1 1,3 1 C _max [nmol/L] average 9 77 117324 --> AUC _0→∞ [nmol·h/l] average 30 358 5379 T _1/2 [hour] average 1,2 2,9 5,4

Pharmacodynamic data:

Significant increases in urinary glucose concentrations have been demonstrated 8 hours after administration at doses >0.01 mg/kg (mean group values: control 1.4 mmol/L; 0.01 mg/kg-1.4 mmol/L; 0.1 mg/kg-46.1 mmol/L; 1mg/kg-239.3mmol/L), and lasted more than 24h.

• None of the three doses of Compound A altered blood glucose levels in cats (compared to normal reference values).

• None of the three doses of Compound A altered kidney function in the cats.

The increase in urinary glucose excretion was clearly dose and plasma compound exposure dependent (log-linear relationship), as shown in Figure 1 .

Example 2: Effect of Compound A on Urine and Blood Glucose after Repeated Dosing in Cats

Compound A was administered to cats that were fasted overnight. Each group (n=3 per group) received oral administration once daily for 3 consecutive days: vehicle alone (PillPocket ^R ), or containing the SGLT2 inhibitor (dry compound) (at 1 mg/kg and 3 mg/kg dose) carrier. Urine glucose and blood glucose were measured.

• A significant increase in urinary glucose concentration has been demonstrated 8 hours after administration of both doses. The maximum urine concentration was further increased after repeated dosing and the doses of 1 mg/kg and 3 mg/kg were similar to each other (means -281 mmol/L and 209 mmol/L, respectively).

• Both doses of Compound A did not alter blood glucose levels in cats (compared to normal reference values).

For urinary glucose excretion, the ED50 was thus estimated to be <1 mg/kg.

Example 3: Effect of Compound A on Urine and Blood Glucose after Repeated Dosing in Cats

Compound A was administered to obese cats with free access to normoglycemia. Individual groups (n=6 per group) received 4 weeks of once-daily oral administration: vehicle alone (gelatin capsules), or vehicle containing the SGLT2 inhibitor (dry compound) at a dose of 1 mg/kg. Urine glucose and blood glucose were measured.

• Significant increase in urinary glucose concentration at the end of the study - control 0.6 mmol/L; 1 mg/kg - 489 mmol/L.

• No changes in blood glucose levels were observed.

Example 4: Treatment of Prediabetes: Prevention of Manifestation of Type 2 Diabetes in Cats

The efficacy of SGLT2 inhibition according to the invention in the treatment of pre-diabetes characterized by fasting glucose and/or glucose intolerance and/or insulin resistance can be tested in clinical studies. In studies of shorter or longer time periods (e.g. 2-4 weeks or 1-2 years), by measuring postprandial or stress testing (oral glucose tolerance test or postprandial The diet glucose value and/or the glucose value after the food tolerance test) and compare them with the value before the start of the study and/or the value of the placebo group to test the success of the treatment. Additionally, fructosamine values can be measured before and after treatment and compared to initial and/or placebo values. Significant reductions in glucose and/or fructosamine levels with or without dieting demonstrate efficacy in the treatment of prediabetes. In addition, the number of patients who developed overt type 2 diabetes was significantly reduced when treated with the pharmaceutical composition of the present invention compared to other treatment modalities, demonstrating efficacy in preventing transition from prediabetes to overt diabetes.

Example 5: Treatment of Prediabetes: Improvement of Insulin Resistance in Cats

The following examples show the beneficial effects of compound A in insulin resistant obese cats. Compound A was administered to insulin resistant obese cats with free access to euglycemia. Individual groups (n=6 per group) received 4 weeks of once-daily oral administration of vehicle alone (gelatin capsules), or vehicle containing the SGLT2 inhibitor (dry compound) at a dose of 1 mg/kg. The following experiments were performed prior to treatment, and after the end of the 4-week treatment period (approximately 24 hours after the last compound/vehicle administration).

In cats on an overnight diet, an intravenous glucose tolerance test (ivGTT, 0.8 g/kg dextrose) was performed. Blood was collected via a jugular catheter. Blood samples were taken at -5, 0, 5, 10, 15, 30, 45, 60, 90, 120, 180 minutes relative to glucose application.

Glucose and insulin excursions were quantified by calculating baseline corrected glucose AUC. In cats on an overnight fast, an intravenous insulin tolerance test (ivITT, 0.05 U/kg regular insulin) was performed. Blood was collected via a jugular catheter. Blood samples were taken at -5, 0, 15, 30, 60, 90, 120, 180 minutes relative to insulin application.

Glucose and non-esterified fatty acid (NEFA) fluctuations were quantified by calculating baseline corrected glucose and NEFAAUC.

Significance of differences in means between groups was assessed by repeated measures two-way (time & treatment) ANOVA with post-hoc multiple comparisons to control or respective baseline readings.

Glucose excursions during the ivGTT did not change over the study period (or due to treatment). In control cats, insulin excursions did not change throughout the study period, but were significantly reduced (p<0.05) compared to baseline values in treated cats.

As shown in Figure 2, in the obese cats used in this study, the insulin secretion profile exhibited a decreased first phase, and an increased and prolonged second phase compared to lean cats. As shown in Figure 2, panel B, treatment with Compound A resulted in a significant improvement in the second phase insulin secretion profile.

Insulin sensitivity was significantly improved compared to baseline in treated cats (p<0.05). This was demonstrated by calculating the relationship between glucose and insulin according to the modified Belfiore index (1/log(ΔAUCgluc*ΔAUCins).

Figure 3 shows the area-under-the-curve values for blood insulin and the blood insulin-versus-glucose relationship expressed by the modified Belfiore index of insulin sensitivity in cats with insulin resistance, where the intravenous glucose tolerance test (ivGTT ) before ("Before") and after 4 weeks of treatment ("After") treatment with Compound A or its vehicle ("Control").

In control animals, glucose excursions during the ivITT were significantly worse (p<0.05) throughout the study period (see Figure 4, panel A). This is also similar for the elimination of NEFA (see Figure 5, panel A). In contrast, in cats treated with Compound A, the glucose profile did not change throughout the study period (see Figure 4, panel B), while Compound A treatment significantly improved NEFA elimination (p<0.01; see Figure 5, panel B ).

These data demonstrate a significant improvement in insulin resistance after 4 weeks of treatment with Compound A in obese cats. Since insulin resistance is a hallmark feature of prediabetes, the data strongly suggest that Compound A is capable of treating prediabetes in felines.

In clinical studies of varying lengths of time (e.g., 2 weeks to 12 months) run in diabetic cats, one can measure baseline blood glucose, blood fructosamine, and blood insulin levels and then monitor how these levels change in individual cats throughout the study period. developed to examine the successful improvement of insulin resistance. Glucose and insulin values after a meal or a stress test (glucose tolerance test or insulin tolerance test) can also be compared with values before the start of the study and/or with diabetes treated with other medications at the end of the study treatment period. The value of cat is compared.

Example 6: Treatment of Type 2 Diabetes in Cats

Treatment of cats with type 2 diabetes with the pharmaceutical composition of the present invention, in addition to producing an acute improvement in glucose metabolic status, also prevents the degradation of metabolic status in the long term. If the cat is treated with the pharmaceutical composition of the present invention for a shorter or longer period (such as 2-4 weeks or 3 months to 1 year), and compared with the metabolic status before treatment or compared with the use of insulin or other antidiabetic drugs This can be observed when comparing treated cats. Evidence of treatment success is provided if mean daily blood glucose and fructosamine levels are reduced compared to pre-treatment levels. Additional evidence of therapeutic success may be obtained if a significantly lower percentage of cats treated with the pharmaceutical composition of the invention have a transient deterioration in the state of glucose metabolism (e.g., hyperglycemia or hypoglycemia) compared to cats treated with other drugs .

Example 7: Improvement of pancreatic beta cell function

In clinical studies of varying lengths of time (e.g., 4 weeks to 12 months) run in diabetic cats, the measurements of baseline blood glucose, blood fructosamine, and blood insulin levels and the corresponding relationships between the parameters were examined in individual cats The success of the treatment. In addition, for example, arginine stimulation can be used to test the ability of pancreatic beta cells to secrete insulin.

During the study or at the end of the study, the increase in blood insulin levels (baseline or after arginine stimulation) compared to the initial value or compared to the placebo group or the group receiving a different treatment demonstrates that the pharmaceutical composition of the present invention Efficacy to Improve Pancreatic Beta Cell Function in Diabetic Cats (Figure 15).

Example 8: Remission of diabetes

In clinical studies run in diabetic cats over a longer period of time (e.g. 3 months to 1 year), using measurements of baseline blood glucose, blood fructosamine and blood insulin levels and the corresponding relationships between the parameters in individual cats, to check the success of the treatment. Evidence of treatment success was provided if laboratory values were reduced compared to pre-treatment levels without insulin injections (Figure 15).

If Compound A is effective in reducing hyperglycemia when administered in combination with, for example, insulin or other drugs, felines can be dispensed with insulin or other drugs and still maintain blood glucose control within the normal range.

Most advantageously, the feline is exempt from Compound A.

Example 9: Reduction of hyperglycemia

In clinical studies of varying lengths of time (eg, 1 day to 12 months) run in diabetic cats, the success of treatment in cats was examined by determining blood glucose or blood fructosamine levels. A significant decrease in these values during the study or at the end of the study, compared to the initial value or compared to the placebo group or the group receiving a different treatment, demonstrates the efficacy of the pharmaceutical composition of the invention in reducing hyperglycemia in cats.

Example 10: Body Composition and Body Fat Reduction

The following examples show the beneficial effects of Compound A in obese cats. Compound A was administered to obese cats fed ad libitum. Individual groups (n=6 per group) received once daily oral administration for 4 weeks: vehicle alone (gelatin capsules), or vehicle containing the SGLT2 inhibitor (dry compound) at a dose of 1 mg/kg. The following experiments were performed prior to treatment, and after the end of the 4-week treatment period (approximately 24 hours after the last compound/vehicle administration). As shown in Figure 6, in treated cats, blood leptin concentrations were significantly reduced throughout the study period (mean: before: 2482 pmol/L, after: 2213 pmol/L, p<0.05).

Indirect calorimetry shows the effect of treatment on energy metabolism. The respiratory exchange rate (RER; the ratio between the amount of exhaled _CO2 and the amount of inhaled _O2 ; see Figure 7) showed a significant increase in fatty acid metabolism (lipid utilization) in treated animals (mean RER values : 0.749 before treatment, 0.728 after treatment; p<0.01).

Increased lipid utilization was also reflected in increased blood β-hydroxybutyrate concentration (β-HB/BHB), as shown in FIG. 8 . The increase in blood β-hydroxybutyrate concentration did not exceed the normal reference value.

Changes in these correlations across the study period showed a significant association and suggested that the treatment showed a beneficial effect on body composition.

Thus, the data showed a positive correlation between changes in blood leptin concentration and changes in RER (before and after 4 weeks of treatment with Compound A) ( FIG. 9 ), as well as blood β-hydroxybutyrate levels (β- HB/BHB) and RER negative correlation (Figure 10).

Liver parameters were unchanged, and no ketones were detected in the urine. Thus, changes in lipid and carbohydrate metabolism were within normal physiological ranges.

As a result, 4 weeks of treatment in obese cats clearly showed amelioration of lipin abnormalities and shifted metabolic substrate utilization from glucose to lipids, representing a clear benefit in the treatment of obese cats. The data strongly suggest that Compound A can treat prediabetes in felines.

Example 11: Pilot Trial of Compound A in Customer-Owned Diabetic Cats

The following data are from 4 diabetic cats prospectively treated with 1 mg/kg of Compound A orally once daily for 28 days. The diagnosis of diabetes is based on: blood glucose >250mg/dl (13.9mmol/L) at screening, glycosuria or serum fructosamine ≥400μmol/L, and at least one clinical symptom/sign coexisting with diabetes[ Persistence of lethargy, polyuria, polydipsia, polyphagia, weight loss, and/or plantigrade posture of the hind legs (DM polyneuropathy)].

The results reflect that at the end of the study, mean (Figure 13) blood glucose values of the 9-hour blood glucose curves were substantially lower in all 4 cats compared to baseline. The reduction was already seen by day 7 and unexpectedly reached a level comparable to long-term insulin therapy. As a comparison, in 14 only use In treated cats, a comparable reduction in mean blood glucose was not observed until day 14 (NADA 141-236, Freedom of Information Summary, Vetsulin). Serum fructosamine confirmed this good glycemic control and also decreased to less than 350 μmol/L on day 28 in all cats (superior control according to laboratory interpretation guidelines) (Figure 14). In contrast, the serum fructosamine of cats treated with Vetsulin was 546 at day 30 and remained elevated to 462 at day 60 (NADA 141-236, Freedom of Information Summary, Vetsulin).

All cats showed improvement in at least one clinical sign/sign, and 3 of 4 cats showed improvement in at least 3 clinical signs/signs (assessed by owner). All cats showed improvements in overall diabetes control (assessed by the investigator). Urinary glucose excretion was reduced in all cats at the end of the study. Hypoglycemia (defined as blood glucose below 70 mg/dL) was not reported.

Taken together, these data demonstrate that Compound A can be used in the treatment of diabetic cats where once-daily oral treatment is equivalent to long-term twice-daily insulin therapy.

Example 12: Preparation of 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranose-1-yl)-benzene (compound A)

The following synthetic examples are used to illustrate the preparation of 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranose-1-yl)-benzene (Compound A) . A method for preparing its crystalline complex with L-proline is also described. It should be considered by way of example only to describe possible approaches, and not to limit the scope of the invention. The terms "room temperature" and "ambient temperature" are used interchangeably and mean a temperature of about 20°C. The following abbreviations are used:

DMF Dimethylformamide

NMPN-methyl-2-pyrrolidone

THF Tetrahydrofuran

Preparation of 4-bromo-3-hydroxymethyl-1-iodo-benzene

Oxalyl chloride (13.0 mL) was added to an ice-cold solution of ₂ -bromo-5-iodo-benzoic acid (49.5 g) in _CH2Cl2 (200 mL). DMF (0.2 mL) was added and the solution was stirred at room temperature for 6 h. Then, the solution was concentrated under reduced pressure and the residue was dissolved in THF (100 mL). The resulting solution was cooled in an ice bath and a portion of LiBH ₄ (3.4 g) was added. The cooling bath was removed and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with THF and treated with 0.1M hydrochloric acid. Next, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (Na ₂ SO ₄ ) and the solvent was allowed to evaporate under reduced pressure to give the crude product.

Yield: 47.0 g (99% of theory)

Preparation of 4-bromo-3-chloromethyl-1-iodo-benzene

Thionyl chloride (13 mL) was added to a suspension of 4-bromo-3-hydroxymethyl-1-iodo-benzene (47.0 g) in dichloromethane (100 mL) containing DMF (0.1 mL). The mixture was stirred at ambient temperature for 3 h. Next, the solvent and excess practical were removed under reduced pressure. The residue was triturated with methanol and dried.

Yield: 41.0 g (82% of theory)

Preparation of 4-bromo-1-iodo-3-phenoxymethyl-benzene

Phenol (13 g) dissolved in 4M KOH solution (60 mL) was added to 4-bromo-3-chloromethyl-1-iodo-benzene (41.0 g) dissolved in acetone (50 mL). NaI (0.5 g) was added and the resulting solution was stirred overnight at 50°C. Next, water was added and the resulting mixture was extracted with ethyl acetate. The combined extracts were dried ( _{Na2SO4 )} and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 19:1).

Yield: 38.0 g (79% of theory)

Preparation of 1-bromo-4-(1-methoxy-D-glucopyranose-1-yl)-2-(phenoxymethyl)-benzene

A 2M solution of iPrMgCl in THF (11 mL) was added to dry LiCl (0.47 g) suspended in THF (11 mL). The mixture was stirred at room temperature until the LiCl was dissolved. This solution was added dropwise to a solution of 4-bromo-1-iodo-3-phenoxymethyl-benzene (8.0 g) in tetrahydrofuran (40 mL) cooled to -60°C under argon. The solution was warmed to -40 °C and then 2,3,4,6-tetra-O-(trimethylsilyl)-D-glucopyrone (10.7 g, 90% pure) in tetrahydrofuran (5 mL) was added . The resulting solution was warmed to -5 °C in a cold bath and stirred at this temperature for an additional 30 min. Water was added as a _NH4Cl solution and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was dissolved in methanol (80 mL) and treated with methanesulfonic acid (0.6 mL) to yield exclusively the more stable anomer. After the solution was stirred overnight at 35-40 °C, the solution was neutralized with solid NaHCO ₃ and methanol was removed under reduced pressure. The remainder was diluted with water in NaHCO ₃ and the resulting mixture was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and the solvent was evaporated to give the crude product (submitted for reduction without further purification).

Yield: 7.8 g (93% of theory)

Preparation of 1-bromo-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranose-1-yl)-2-(phenoxymethyl)-benzene

Boron trifluoride diethyl etherate (4.9 mL) was added to 1-bromo-4-(1-methoxy-D-glucopyranose-1-yl)-2-(phenoxymethyl)-benzene (8.7 g) and triethylsilane (9.1 mL) in dichloromethane (35 mL) and acetonitrile (50 mL) cooled to -20°C at a rate of addition such that the temperature was maintained at -10°C. The resulting solution was warmed to 0 °C over a period of 1.5 h and then treated with aqueous sodium bicarbonate solution. The resulting mixture was stirred for 0.5 h, the organic solvent was removed, and the residue was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, and the solvent was removed. The residue was extracted in dichloromethane (50 mL) and pyridine (9.4 mL), and acetic anhydride (9.3 mL) and 4-dimethylaminopyridine (0.5 g) were successively added to the solution. The solution was stirred at ambient temperature for 1.5 h and then diluted with dichloromethane. The solution was washed twice with 1M hydrochloric acid and dried over sodium sulfate. After removal of the solvent, the residue was recrystallized from ethanol to provide the product as a colorless solid.

Yield: 6.78 g (60% of theory)

Mass spectrum (ESI ⁺ ): m/z=610/612(Br)[M+NH ₄ ] ⁺

Preparation of 2-(phenoxymethyl)-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranose-1-yl)-benzocyanide

Flush with argon charged with zinc cyanide (1.0g), zinc (30mg), Pd ₂ (dibenzylidene acetone) ₃ * CHCl ₃ (141 mg) and tri-tert-butylphosphonium tetrafluoroboric acid (111 mg) flask. Then 1-bromo-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranose-1-yl)-2-(phenoxymethyl)-benzene (5.4 g) was added in NMP (12 mL), and the resulting mixture was stirred at room temperature for 18 h. After dilution with ethyl acetate, the mixture was filtered and the filter was washed with water as a sodium bicarbonate solution. The organic phase was dried (sodium sulfate) and the solvent was removed. The residue was recrystallized from ethanol.

Yield: 4.10 g (84% of theory)

Mass spectrum (ESI ⁺ ): m/z=557[M+NH ₄ ] ⁺

Alternatively, starting from 1-bromo-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranose-1-yl)-2-(phenoxymethyl)-benzene with cyanide Copper(I) (2 equivalents) was used to synthesize the above compounds in NMP at 210°C.

Preparation of 2-bromomethyl-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranose-1-yl)-benzocyanide

A 33% solution of hydrobromic acid in acetic acid (15 mL) was added to 2-phenoxymethyl-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranose-1- In a solution of benzocyanide (0.71 g) and acetic anhydride (0.12 mL) in acetic acid (10 mL). The resulting solution was stirred at 55 °C for 6 h and then cooled in an ice bath. The reaction mixture was neutralized with ice-cold aqueous potassium carbonate solution, and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was extracted in ethyl acetate/cyclohexane (1:5) and the precipitate was isolated by filtration and dried at 50°C to afford pure product.

Yield: 0.52 g (75% of theory)

Mass spectrum (ESI ⁺ ): m/z=543/545(Br)[M+NH ₄ ] ⁺

Preparation of 4-cyclopropyl-phenylboronic acid

A 2.5M solution of n-butyllithium in hexane (14.5 mL) was added dropwise to 1-bromo-4-cyclopropyl-benzene (5.92 g) dissolved in THF (14 mL) and toluene (50 mL) , and cooled to -70°C. The resulting solution was stirred at -70 °C for 30 min before addition of triisopropyl borate (8.5 mL). The solution was warmed to -20°C and then treated with 4M aqueous hydrochloric acid (15.5 mL). The reaction mixture was further warmed to room temperature, and then the organic phase was separated. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried (sodium sulfate). The solvent was evaporated and the residue was washed with a mixture of diethyl ether and cyclohexane to give the product as a colorless solid.

Yield: 2.92 g (60% of theory)

Mass spectrum (ESI ^- ): m/z=207(Cl)[M+HCOO] ^-

Preparation of 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranose-1-yl)-benzene

An Ar-filled flask was charged with 2-bromomethyl-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranose-1-yl)-benzocyanide (1.60 g), 4-Cyclopropyl-phenylboronic acid (1.0 g), potassium carbonate (1.85 g) and a degassed 3:1 mixture of acetone and water (22 mL). The mixture was stirred at room temperature for 5 min before cooling in an ice bath. Palladium dichloride (30 mg) was then added and the reaction mixture was stirred at ambient temperature for 16 h. The mixture was then diluted with brine and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was dissolved in methanol (20 mL) and treated with 4M aqueous potassium hydroxide solution (4 mL). The resulting solution was stirred at ambient temperature for 1 h and then neutralized with 1M hydrochloric acid. Methanol was evaporated and the residue was diluted with brine and extracted with ethyl acetate. The organic extract of the mobile phone was dried over sodium sulfate and the solvent was removed. The residue was chromatographed on silica gel (dichloromethane/methanol 1:0 -> 8:1).

Yield: 0.91 g (76% of theory)

Mass spectrum (ESI ⁺ ): m/z=413[M+NH ₄ ] ⁺

Preparation of the crystalline complex (1:1) of compound A and L-proline

To 1-cyano-2-(4-cyclopropyl-benzyl)-4- A solution of (β-D-glucopyranose-1-yl)-benzene (1.17 g, obtained as described above) was dissolved in 2 mL of ethanol. The resulting solution was allowed to stand at ambient temperature. After approximately 16 h, the crystalline complex was isolated as white crystals by filtration. Crystallization may be initiated, if necessary, by scratching with a glass rod or metal spatula, or by seeding, for example. Residual solvent was removed by storing the crystals at slightly elevated temperature (30 to 50° C.) under vacuum for approximately 4 h to yield 1.27 g of crystals in a 1:1 mixture (L-proline with 1-cyano-2-(4 -cyclopropyl-benzyl)-4-(β-D-glucopyranose-1-yl)-benzene.

Several batches of crystalline complexes of the above formulations were obtained. The X-ray powder diffraction pattern is consistent. Melting points were determined by DSC and evaluated as onset temperatures. Examples of melting points are about 89°C, 90°C, 92°C, 101°C and 110°C. The X-ray powder diffraction patterns contained in Table 1 and shown in Figure 11, and the DSC and TG patterns in Figure 12 correspond to batches with a melting point of approximately 90°C.

The X-ray powder diffraction pattern (peaks in 2Θ up to 30°) of the crystalline complex of Compound A with L-proline is given in Table 1 above.

Example 13: Formulation

Some examples of formulations are described, wherein the term "active substance" denotes a SGLT2 inhibitor or a pharmaceutically acceptable form thereof, such as a prodrug or crystalline form, for use in the present invention. Where one or another active substance is combined, the term "active substance" may also include the additional active substance.

Tablets containing 100 mg of active substance

Element:

1 tablet contains:

Preparation:

The active substance, lactose and starch are mixed together and moistened evenly with an aqueous solution of polyvinylpyrrolidone. After the wet composition was sieved (mesh size 2.0 mm) and dried in a rack dryer at 50° C., it was sieved again (mesh size 1.5 mm) and the lubricant was added. The finished mixture is compressed to form tablets.

Tablet Weight: 220mg

Diameter: 10mm, double flat, with facets on both sides and notches on one side.

Tablets containing 150 mg of active substance

Element:

1 tablet contains:

preparation:

The active mixed with lactose, cornstarch and silica is moistened with a 20% aqueous solution of polyvinylpyrrolidone and passed through a 1.5 mm mesh size sieve. The granules dried at 45°C were again passed through the same sieve and mixed with the indicated amount of magnesium stearate. Tablets are compressed from the mixture.

Tablet Weight: 300mg

Mold (die): 10mm, flat

Hard gelatin capsule containing 150 mg of active substance

Element:

1 capsule contains:

preparation:

The active substance is mixed with the excipients, passed through a sieve with a mesh size of 0.75 mm and mixed homogeneously using suitable equipment. The finished mixture is encapsulated into size 1 hard gelatin capsules.

Capsule Filler: about 320mg

Capsule Shell: Size 1 hard gelatin capsule.

Suppository containing 150 mg of active substance

Element:

1 suppository contains:

preparation:

After the suppository mass has melted, the active substance is distributed uniformly therein, and the melt is poured into cooled molds.

Ampoule containing 10 mg of active substance

Element:

Active substance 10.0mg

0.01N hydrochloric acid/NaCl appropriate amount

Add double distilled water to 2.0ml

preparation:

The active substance is dissolved in the necessary amount of 0.01N HCl, made isotonic with common salt, filter sterilized and transferred to 2 ml ampoules.

Ampoule containing 50 mg of active substance

Element:

Active substance 50.0 mg

0.01N hydrochloric acid/NaCl appropriate amount

Add double distilled water to 10.0ml

preparation:

The active substance is dissolved in the necessary amount of 0.01N HCl, made isotonic with common salt, filter sterilized and transferred to 10 ml ampoules.

references

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(6) Hoenig, Mol Cell Endocrinol 2002, 197(1-2): 221-229

(7) Hoenig et al., AmJ Physiol, 2011, 301(6): R1798-1807

(8) NADA141-236 Freedom of Information Vetsulin

(9) PalmCA et al., VetClinSmallAnim2013, 43:407-415

(10) Reusch CE et al., Schweizer Archivfuer Tierheilkunde 2011, 153811): 495-500

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(12) Verbrugghe et al., CritRevFoodSciNutr.2012;52(2):172-182

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Claims (16)

1. one or more SGLT2 inhibitor or its pharmaceutically acceptable form, its purposes is for treating and/or preventing the metabolism disorder in felid.

2. it is used for one or more SGLT2 inhibitor or its pharmaceutically acceptable form of the purposes of claim 1, wherein said metabolism disorder is selected from following one or more: ketoacidosis, prediabetes, 1 type or type 2 diabetes mellitus, insulin resistant, obesity, hyperglycemia, glucose intolerance, hyperinsulinemia, dyslipidemia, blood fat element is abnormal, Sub-clinical inflammation, systemic inflammatory, low systemic inflammatory, liver lipidosis, atherosclerosis, pancreas inflammatory, neuropathy and/or X syndrome (metabolism syndrome) and/or Pancreatic beta cells function are lost,

And/or wherein realize and/or keep the alleviation of metabolism disorder, preferred insulin to alleviate.

3. for one or more SGLT2 inhibitor or its pharmaceutically acceptable form of the purposes any one of claim 1-2, wherein said metabolism disorder is prediabetes, type 1 diabetes or type 2 diabetes mellitus and/or the clinical symptom being associated with prediabetes, type 1 diabetes or type 2 diabetes mellitus, preferably prediabetes or type 2 diabetes mellitus and/or the clinical symptom being associated with prediabetes or type 2 diabetes mellitus.

4. for one or more SGLT2 inhibitor of purposes or its pharmaceutically acceptable form of claim 3, wherein said clinical symptom is selected from following one or more: ketoacidosis, insulin resistant, obesity, hyperglycemia, glucose intolerance, hyperinsulinemia, dyslipidemia, blood fat element exception, Sub-clinical inflammation, systemic inflammatory, low systemic inflammatory, liver lipidosis, atherosclerosis, pancreas inflammatory, neuropathy and/or X syndrome (metabolism syndrome) and/or Pancreatic beta cells function is lost and/or diabetes alleviation.

5. for one or more SGLT2 inhibitor or its pharmaceutically acceptable form of the purposes any one of claim 2-4, wherein said ketoacidosis, insulin resistant, obesity, hyperglycemia, glucose intolerance, hyperinsulinemia, dyslipidemia, blood fat element is abnormal, Sub-clinical inflammation, systemic inflammatory, low systemic inflammatory, liver lipidosis, atherosclerosis, pancreas inflammatory, neuropathy and/or X syndrome (metabolism syndrome) and/or Pancreatic beta cells function are lost and/or diabetes alleviation is associated with diabetes, preferably it is associated with prediabetes or type 2 diabetes mellitus.

6., for one or more SGLT2 inhibitor or its pharmaceutically acceptable form of the purposes any one of claim 1-5, wherein said felid is fat.

7., for one or more SGLT2 inhibitor or its pharmaceutically acceptable form of the purposes any one of claim 1-6, wherein said felid suffers from diabetes, preferably prediabetes or type 2 diabetes mellitus.

8., for one or more SGLT2 inhibitor or its pharmaceutically acceptable form of the purposes any one of claim 1-7, wherein said felid is cat.

9. for one or more SGLT2 inhibitor or its pharmaceutically acceptable form of purposes any one of claim 1-8, wherein its pharmaceutically acceptable form be one or more SGLT2 inhibitor described or its pharmaceutically acceptable form and one or more aminoacid, crystalline composites between preferred proline, more preferably L-PROLINE.

10. for one or more SGLT2 inhibitor or its pharmaceutically acceptable form of the purposes any one of claim 1-9, wherein this kind of 1-cyano group-2-(4-cyclopropyl-benzyl)-4-(β-D-Glucopyranose .-1-base)-benzene or its pharmaceutically acceptable form are wanted Orally administered or use without intestinal, and preferred oral is used.

11. one or more SGLT2 inhibitor being used for the purposes any one of claim 1-10 or its pharmaceutically acceptable forms, wherein this type of one or more SGLT2 inhibitor or its pharmaceutically acceptable form to be used with the dosage of 0.01 to 5.0mg/kg body weight every day, preferably use with the dosage of 0.01 to 3.0mg/ body weight every day, more preferably use with the dosage of 0.1 to 3.0mg/kg body weight every day, more preferably to use with the dosage of 0.2 to 2.0mg/kg body weight every day, most preferably use with the dosage of 0.3 to 1.0mg/kg every day.

12. one or more SGLT2 inhibitor being used for the purposes any one of claim 1-11 or its pharmaceutically acceptable forms, wherein this type of one or more SGLT2 inhibitor or its pharmaceutically acceptable form are only used once every day.

13. one or more SGLT2 inhibitor being used for the purposes any one of claim 1-12 or its pharmaceutically acceptable forms, wherein this type of one or more SGLT2 inhibitor or its pharmaceutically acceptable form are used with insulins combinations.

14. one or more SGLT2 inhibitor being used for the purposes any one of claim 1-13 or its pharmaceutically acceptable forms, one or more SGLT2 inhibitor wherein said is glucopyranosyl-substituted benzene derivative.

15. one or more SGLT2 inhibitor being used for the purposes any one of claim 1-13 or its pharmaceutically acceptable forms, one or more SGLT2 inhibitor wherein said is selected from:

(1) glucopyranosyl of chemical formula (1)-substituted benzene derivative

Wherein R¹Represent cyano group, chlorine or methyl；

R²Represent H, methyl, methoxyl group or hydroxyl；With

R³nullRepresent cyclopropyl、Hydrogen、Fluorine、Chlorine、Bromine、Iodine、Methyl、Ethyl、Propyl group、Isopropyl、Butyl、Sec-butyl、Isobutyl group、The tert-butyl group、3-methyl-butyl-1-base、Cyclobutyl、Cyclopenta、Cyclohexyl、1-hydroxy-cyclopropyl、1-hydroxy-cyclobutyl、1-hydroxy-cyclope、1-hydroxy-cyciohexyl、Acetenyl、Ethyoxyl、Difluoromethyl、Trifluoromethyl、Pentafluoroethyl group、2-hydroxy-ethyl、Methylol、3-hydroxyl-propyl、2-hydroxy-2-methyl-propyl-1-base、3-hydroxy-3-methyl-butyl-1-base、1-hydroxyl-1-methyl-ethyl、2,2,2-tri-fluoro-1-hydroxyl-1-methyl-ethyl、2,2,2-tri-fluoro-1-hydroxyl-1-trifluoromethyl-ethyl、2-methox-etlayl、2-ethoxy-ethyl、Hydroxyl、Difluoro-methoxy、Trifluoromethoxy、2-Mehtoxy-ethoxy、Methylsulfanyl、Methylsulfinyl、Methyl sulphonyl、Ethylsulfinyl、Ethylsulfonyl、Trimethyl is silica-based、(R)-oxolane-3-base oxygen or (S)-oxolane-3-base oxygen or cyano group，

Or one or more oh group of its derivant wherein β-D-glucopyranosyl group is selected from following group acylation: (C_1-18-alkyl) carbonyl, (C_1-18-alkyl) oxygen carbonyl, phenylcarbonyl group and phenyl-(C_1-3-alkyl)-carbonyl；

(2) 1-cyano group-2-(4-cyclopropyl-benzyl)-4-(β-D-Glucopyranose .-1-base)-benzene, is represented by chemical formula (2):

(3) Da Gelie is clean, chemical formula (3) represent:

(4) canagliflozin, is represented by chemical formula (4):

(6) glug row are clean, chemical formula (6) represent:

(7) Tuo Gelie is clean, chemical formula (7) represent:

(8) Yi Gelie is clean, chemical formula (8) represent:

(9) Ai Gelie is clean, chemical formula (9) represent:

(10) A Gelie is clean, chemical formula (10) represent:

(11) Rui Gelie is clean, chemical formula (11) represent:

(12) thiophene derivant of chemical formula (12):

Wherein R represents methoxyl group or trifluoromethoxy；

(13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thenyl] benzene, is represented by chemical formula (13):

(14) the spiroketal derivant of chemical formula (14):

Wherein R represents methoxyl group, trifluoromethoxy, ethyoxyl, ethyl, isopropyl or the tert-butyl group；

(15) pyrazole-O-glycoside derivatives of chemical formula (15)

Wherein

R¹Represent C_1-3-alkoxyl,

L¹, L²Represent H or F independently of one another,

R⁶Represent H, (C_1-3-alkyl) carbonyl, (C_1-6-alkyl) oxygen carbonyl, carbobenzoxy, benzyloxycarbonyl group or benzyloxycarbonyl group；

(16) compound of chemical formula (16):

(17) She Gelie is clean, chemical formula (17) represent:

(18) compound represented by chemical formula (18):

Wherein

R³Selected from cyclopropyl, ethyl, acetenyl, ethyoxyl, (R)-oxolane-3-base oxygen or (S)-oxolane-3-base oxygen.

16. pharmaceutical compositions, it comprises according to one or more SGLT2 inhibitor any one of claim 1-15 or its pharmaceutically acceptable form, for according to the purposes any one of claim 1-15.